Hematologist
THE
A S H® N E W S A N D R E P O R T S
JULY/AUGUST 2008
VOLUME 5 ISSUE 4
IOM SEEKS ASH TESTIMONY ON CONFLICT OF INTEREST
KENNETH KAUSHANSKY, MD, FACP
FEATURES
Dr. Kaushansky is Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego. Dr.
Kaushansky is President of ASH.
OP-ED: THE HEPARIN
WOES – Drs. Raj S.
Kasthuri and Nigel S. Key
review the latest news in this
developing situation.
n May 22, 2008, I presented oral testimony to the
Institute of Medicine (IOM) on conflicts of interest
between medical societies and the pharmaceutical industr y
and the policies that ASH has put in place to safeguard against
introducing bias into our meetings, publications, and positions.
ASH has developed policies that preser ve the scientific integrity
of the discipline while productively interacting with industr y.
ing of the Clinical Research Training Institute, but because of
their knowledge of the drug development process, speakers who
work for a pharmaceutical company may be included as faculty at
the week-long initiation meeting. Another special circumstance is
the development of clinical guidelines. Individuals with recent, relevant financial conflicts are prohibited from ser ving as a member
of a clinical guideline writing committee.
The Society ’s policies concerning conflict of interest have evolved
over time. ASH uses disclosure and peer review to identify conflicts and then manages them. For example, at this year ’s annual
meeting, individuals invited to speak will be prohibited from also
speaking at a corporate symposium. This decision was made to
prevent the appearance of conflict that could result from having a
speaker present at both a corporate-sponsored symposium and an
ASH educational session. And, the Society now requires ever y
committee chair to appoint a conflict-of-interest compliance officer.
ASH agrees with the AAMC that conflicts of interest extend to
all phases of biomedical research. Thus, at the Clinical Research
Training Institute, faculty discuss how, in preclinical research,
financial conflicts can lead to bias. This includes clinical or translational research that may become a component of an IND submission or lead to research involving humans.
O
From time to time, the target audience requires special treatment.
No corporate contributions have been sought or obtained for fund-
For more information, read the written testimony submitted to the
IOM at www.hematology.org/policy/testimony/IOM.pdf. One
important note to mention is that ASH is developing a centralized,
Web-based conflict-of-interest registr y that will be fully online no
later than 2010.
2
ASK THE
HEMATOLOGIST – Dr.
Craig Kessler shares
treatment options for a 61year-old man with recentonset atrial fibrillation.
4
MINI REVIEW: MOUSE
MODELS OF LEUKEMIA:
PROS AND CONS – Drs.
Benjamin S. Braun, Scott W.
Lowe, and Kevin Shannon
address the role of mouse
models of cancer in developing and testing new therapies.
5
ASH: A GLOBAL
SOCIETY – A guide to
myths and facts about
international membership in
ASH.
7
D I F F U S I O N
Genes to Tailor Warfarin Dosage
Schwarz UI, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358:999-1008.
ow much would you pay to know your patient’s
response to warfarin before you even gave the first
dose? This question may be more than academic as
accumulating data indicate that gene variants of enzymes
mediating the pharmacokinetics and pharmacodynamics of
warfarin are predictive of an individual patient’s response
to warfarin.
H
with somewhat shor ter times to first INR >4 than the
CYP2C9*1 variant. Thus, genetic variability in VKORC1 is
more closely associated with initial sensitivity to warfarin
than genetic variability in CYP2C9.
Studies have focused primarily on two genes. VKORC1
encodes vitamin K epoxide reductase, which recycles vitamin K epoxide to the reduced form of vitamin K and is the
major target of warfarin. Individuals with different VKORC1
haplotypes require different doses of warfarin for therapeutic anticoagulation. CYP2C9 encodes cytochrome P-450
2C9, the primary enzyme required for metabolic clearance
of warfarin. Polymorphisms of CYP2C9 also contribute to
variability in sensitivity to warfarin. In a recent prospective
study, Schwarz and colleagues evaluated the association of
variants of VKORC1 and CYP2C9 with changes in INR following initiation of warfarin therapy.
Warfarin remains the most widely used oral anticoagulant
for patients with venous thromboembolic disease. However,
its narrow therapeutic window is a substantial liability
because supratherapeutic anticoagulation can result in
bleeding, subtherapeutic anticoagulation is a risk for thrombosis, and there is a wide variation in individual dose
requirements. The ability to predict an individual patient’s
response to warfarin therapy a priori could reduce the time
to achieve a therapeutic INR, increase time within the therapeutic range, and potentially reduce bleeding and recurrent thrombotic episodes. This study demonstrates that
genetic variants of VKORC1 constitute a significant determinant of initial response to warfarin therapy. Screening for
VKORC1 haplotypes may improve warfarin dosing algorithms.
Bleeding risk associated with warfarin therapy is relatively
greater in the first month of therapy. Among the primary
outcomes evaluated by Schwarz, et al. was the association
of gene variants of VKORC1 and CYP2C9 with the first INR
within therapeutic range and time to first INR >4. The rate
of achieving the first INR in therapeutic range was higher
by nearly 2.4-fold in patients with the A/A haplotype of
VKORC1 compared with non-A haplotypes. The rate to first
INR >4 was increased by >2.5-fold in patients with the A/A
haplotype. Rates for achieving these endpoints were even
increased in patients with a single A allele. CYP2C9 polymorphisms had less influence on initial response to warfarin. No effect on time to first therapeutic INR was detected. CYP2C9*2 and CYP2C9*3 variants were associated
The FDA has recently updated the label of warfarin to
encourage pharmacogenetic testing to help guide dosing of
individuals initiating warfarin therapy. As information on the
role of genetic profiling for warfarin therapy becomes available, the impact of such screening to improve efficacy and
safety will be subject to increasing scrutiny. Is the screening cost-effective? Should all patients be screened? Should
we test only subpopulations at substantial risk for bleeding
or clotting? Can test results be obtained rapidly enough to
influence initial dosing? Genetic screening to improve warfarin therapy may or may not find a role in the routine management of patients with thrombotic disease. However, it
has already proven to be an impor tant test case in the nascent field of pharmacogenetics.
PATIENTS AND
POLITICS – Dr.
Margaret Ragni highlights efforts to develop a
patient-focused guide about
the upcoming presidential
election.
14
WILLIAM DAMESHEK:
COMPASSIONATE
CLINICIAN AND
GIFTED TEACHER – Dr.
Robert S. Schwartz reflects
on the career of this prominent hematologist.
15
DEPARTMENTS
3
NEWS AND REPORTS
4
THE PRACTICING
HEMATOLOGIST
6
THE HEMATOLOGIST
ADVOCATE
7
THE INTERNATIONAL
8
DIFFUSION
13
THE HEMATOLOGIST-IN-
HEMATOLOGIST
TRAINING
15
ASH’S 50TH:
PROFILES IN
HEMATOLOGY
16
MARK YOUR
CALENDAR
ROBERT FLAUMENHAFT, MD, PhD
Dr. Flaumenhaft indicated no relevant conflicts of interest.
O P - E D
The materials comprising the Op-Eds for The Hematologist are provided on an “as-is, as-available” basis for informational purposes only. These
materials do not necessarily represent the opinions, beliefs, or positions of The Hematologist, which is not responsible for any errors or omissions in the materials. The Hematologist welcomes Op-Ed pieces or letters to the editor on any subject.
THE HEPARIN WOES: CONTAMINATION, CONTACT ACTIVATION,
REGULATION, AND LEGISLATION
RAJ S. KASTHURI, MD, MBBS, AND NIGEL S. KEY, MBChB, FRCP
Dr. Kasthuri is Assistant Professor of Medicine at the University of North Carolina School of Medicine.
Dr. Key is Harold R. Roberts Distinguished Professor and Director of the Hemophilia and Thrombosis Center at the University of North Carolina School of Medicine.
eparin has been in the spotlight recently. The U.S. Food and Drug
Administration (FDA) began receiving reports of allergic reactions to
heparin in Januar y 2008. The extent and significance of the problem
have become increasingly clear over the subsequent months, and it has been the
topic of much news and debate.
H
The FDA has received reports of 131 deaths among individuals exposed to
heparin between Januar y 2007 and April 13, 2008. Of these, 81 deaths were
thought to be linked to heparin use, given the reported clinical syndromes of allergic reactions/hypotension. Hundreds of cases of non-fatal allergic reactions have
also been reported in the United States and in 10 other countries worldwide.
Following the initial reports of adverse outcomes, Baxter Healthcare Corporation,
the supplier of the majority of heparin in the United States, recalled all heparin
formulations in Februar y. Covidien and B. Braun, other companies that supply
heparin in the United States, subsequently issued heparin recalls in March.
More recently, Medtronic (makers of heparin-coated medical devices) and Atrium
Medical Corporation (makers of heparin-coated drainage catheters) have also
issued product recalls.
Heparin is prepared from porcine intestinal mucous membranes. The active ingredient of heparin manufactured by many companies is produced in China, where
the initial steps of procuring the active ingredient occurs at unregulated “workshops,” often run as family operations before being sold to larger manufacturing
plants via “consolidators.” Contamination of heparin with over-sulfated chon-
droitin sulfate (OSCS) at some early point in this manufacturing “pipeline” has
been identified as the cause of the allergic phenomena. While chondroitin sulfate
is also a glycosaminoglycan, it does not occur naturally in the over-sulfated form
that is structurally similar to heparin.
A group of researchers led by Dr. R am Sasisekharan at the Massachusetts
Institute of Technology investigated the link between OSCS and the reported
allergic reactions. Heparin lots were procured from the FDA (13 associated with
adverse events, 16 without) and analyzed for the presence of OSCS in a blinded
fashion. All 13 heparin lots associated with adverse events showed evidence of
contamination with OSCS ranging from 2 percent to 27 percent of the total glycosaminoglycan content. The contaminated heparin samples also demonstrated the
ability to activate the kinin contact system (kallikrein activation) while natural
chondroitin sulfate A did not. Additionally, contaminated heparin induced the
production of complement C5a, which was dependent on activation of the contact
system via factor XII activation. These findings were confirmed in a pig model by
infusion of both contaminated and control heparin, as well as synthetic OSCS.
While the animal studies showed induction of kallikrein with contaminated
heparins, it did not always result in clinical manifestations, suggesting a possible
role for presence of additional risk factors and variations in regulator y mechanisms. These findings may also explain why certain subsets of patients, such as
those receiving hemodialysis, may be more susceptible to adverse outcomes. The
results of these studies were recently published in the New England Journal of
Medicine, 1 and the authors should be commended for their contributions.
(Cont. on Page 4)
A S H R e c o g n i z e d o n U . S . H o u s e o f R e p r e s e n t a ti v e s F lo o r f o r
A c c o m p l is h m e n ts in t h e A r e a o f S t e m C e ll R e s e a r c h
On Wednesday, April 23, 2008, Representative Michael N. Castle (R-DE) congratulated ASH on its 50th anniversary during a speech on the floor of the U.S. House of
Representatives. Representative Castle recognized the many accomplishments of hematologists in the area of stem cell research, an area in which he has led efforts to expand
federal funding through his sponsorship of the Stem Cell Research Enhancement Act
(H.R. 3). Below is the text of his speech as published in the Congressional Record.
M
adam Speaker, I rise today to offer my congratulations to the American
Society of Hematology (ASH) on its 50th anniversar y and to recognize
some of the many contributions made by hematology researchers.
I have had the opportunity to work closely with ASH researchers over the past several years while seeking to expand federally funded stem cell research. Highlighting the
significance of embr yonic stem cell research will remain one of my top issues as millions of Americans continue to suffer from debilitating diseases that could potentially
be helped through this life-saving research.
Hematologists have pioneered the field of stem cell research for over 40 years with
innovative discoveries about adult bone marrow stem cells and how they could be
used to cure human diseases. Today, hematopoietic stem cell transplantation
(HSCT) is an important approach for treating blood and bone marrow disorders as
well as certain types of cancer. The earliest work with HSCT began in the 1950s.
By the 1960s, this treatment was successfully used in patients with end-stage
leukemia. Subsequent research in this area has led to improved transplantation techniques and improved sur vival rates for a number of diseases.
ASH was one of the first professional medical or scientific organizations to issue a
statement in support of all avenues of stem cell research. Today, ASH members are
poised to contribute to research on embr yonic stem cells that has the potential to lead
to the next generation of important therapies for a broad range of diseases.
CORRECTION
It was brought to our attention that Dr. Ernst Jaffé did not take over editorship of Blood from William Dameshek in 1974, as mentioned in the
May/June 2008 memorial article on Dr. Jaffé. Dr. Dameshek died in
1969. The editor of Blood who preceded Dr. Jaffé was Dr. Frederick
Stohlman, Jr.
LETTERS TO THE EDITOR — SOLICITATION
The Hematologist welcomes letters of up to 200 words. These letters may
be in response to editorials or on any subject of interest to our readers.
Please include a postal address, e-mail address, and phone number.
Publication will be based on editorial decisions regarding interest to readers and space availability. We may edit letters for reasons of space or
clarity. The Hematologist reserves the right to publish your letter, unless it
is labeled “not for publication.”
Letters should be sent to:
Karen Learner, Managing Editor
The Hematologist: ASH News and Reports
1900 M Street, NW, Suite 200
Washington, DC 20036
[email protected]
I look for ward to continuing to work with ASH and its members in the future and
congratulate the Society again on its 50 years of research contributions.
2
The Hematologist: ASH NEWS AND REPORTS
N E W S
A N D
R E P O R T S
Hematologist
THE
ASH ® NEWS AND REPORTS
ISSN 1551-8779
Editor-in-Chief
Peter Emanuel, MD
Winthrop P. Rockefeller Cancer Institute
Little Rock, AR
Contributing Editors
Charles Abrams, MD
University of Pennsylvania
School of Medicine
Philadelphia, PA
Election Ballots to Mail in August
Active members in good standing will receive
election materials by mail in late August for this
year’s ASH leadership election for Vice
President, Secretary, and three Councillors.
Ballots are due by September 30, and the
results of the election will be announced in the
November/December issue of The
Hematologist.
Kenneth Anderson, MD
Dana-Farber Cancer Institute
Boston, MA
John Byrd, MD
The Ohio State University
Columbus, OH
Nelson Chao, MD
Duke University Medical Center
Durham, NC
Robert Flaumenhaft, MD, PhD
Harvard Medical School
Boston, MA
Steven Grant, MD
Virginia Commonwealth University
Richmond, VA
Diane Krause MD, PhD
Yale University School of Medicine
New Haven, CT
Trainee Research Award
Recipients Announced
ASH is proud to announce the 2008 recipients
of its Trainee Research Awards. Forty medical
students, undergraduates, and residents will
each receive $4,000 to conduct research on
blood and blood-related diseases through this
program, which is designed to encourage the
pursuit of research and spark an interest in
hematology. To see the list of names, go to
www.hematology.org/media/05062008.cfm.
IMPORTANT ANNUAL MEETING DATES
June 23:
Abstract submission system opens online.
July 22:
Early-bird registration opens for ASH members.
ASH members who have paid their dues for
2008 are eligible for early-bird registration.
Early-bird registration is available online only;
registration forms cannot be faxed or mailed.
ASH members can register for the annual meeting and make hotel reservations at www.hematology.org. Please note that you must register
for the annual meeting in order to make a hotel
reservation.
August 5:
Annual meeting advance registration opens to
members and non-members.
August 21:
Abstract submission deadline.
Michael Linenberger, MD, FACP
Seattle Cancer Center Alliance
Seattle, WA
Charles Parker, MD
University of Utah
Salt Lake City, UT
Josef Prchal, MD
University of Utah
Salt Lake City, UT
Jerald Radich, MD
Fred Hutchinson Cancer Research Ctr.
Seattle, WA
Gérard Socié, MD, PhD
St. Louis Hospital-1
Paris, France
ASH Member Elected to the
National Academy of Sciences
Ronald Levy, MD
Professor of Medicine, Robert K. Summy and
Helen K. Summy Professor, and Chief of the
Division of Oncology at Stanford University
School of Medicine
ASH Members Named Fellows of the
American Academy of
Arts and Sciences
Jerome Groopman, MD
Professor of Medicine at Harvard Medical
School and Chief of Experimental Medicine at
Beth Israel Deaconess Medical Center
Managing Editor
Karen Learner
Graphic Designer
Michael Kelly
American Society of Hematology
1900 M Street, NW, Suite 200
Washington, DC 20036
[email protected]
©2008 by the American Society of
Hematology.
All materials contained in this newsletter
are protected by copyright laws and may
not be used, reproduced, or otherwise
exploited in any manner without the express
prior written permission of The Hematologist:
ASH News and Reports. Any third party
materials communicated to The
Hematologist become its copyrighted property and may be used, reproduced, or otherwise exploited by The Hematologist.
Judy Lieberman, PhD, MD
Senior Investigator at the Immune Disease
Institute, Professor of Pediatrics, and Director,
Division of AIDS, at Harvard Medical School
Attention Trainees:
This One’s for You
This year’s Trainee Day will take place on Friday,
December 5, 2008, from 7:00 a.m. to 12:00
noon. This half-day workshop is designed to support and encourage trainees in the field of academic hematology and to enhance their career
development. The program will be presented
through didactic and interactive small-group
breakout sessions that will provide attendees
with time for discussion, questions, and
answers.
Didactic sessions will include:
• Defining the Research Hypothesis/Question
• How to Identify and Pursue Appropriate
Funding for Your Research
Small-group breakout sessions will include:
Samuel I. Rapaport, MD
Emeritus Professor of Medicine and Pathology
and Former Director of the Hemostasis and
Thrombosis Research Laboratory at University
of California, San Diego School of Medicine
Leonard I. Zon, MD
Howard Hughes Medical Institute Investigator,
and Grousbeck Professor of Pediatric Medicine
at Children’s Hospital Boston of Harvard Medical
School
• Developing Collaborative Research Teams
• Identifying and Pursuing Post-Training Career
Opportunities
Trainee Day is limited to 200 participants; preregistration is required and will begin in August.
E-mail [email protected] for more information.
Contributing authors have declared any
financial interest in a product or in potentially competing products, regardless of the
dollar amount. Any such financial interest is
noted at the bottom of the article.
The Hematologist: ASH NEWS AND REPORTS
3
T H E
THE HEPARIN WOES
(Cont. from Page 2)
Investigations into the source of this contamination have
revealed many irregularities in the manufacturing “pipeline.”
It appears that the contamination of heparin was intentional,
as OSCS does not occur naturally. The lack of regulation of
overseas manufacturing plants, as well as the FDA itself, has
come under significant criticism. It is apparent that current
budget restrictions significantly limit the capabilities of this
organization to inspect foreign manufacturing plants (>500)
ever y two years — the norm within the United States. This
issue has received considerable attention within the House and
the Senate in the last few months, and whether this will result
in implementation of useful steps to prevent such tragedies
from occurring again remains to be seen.
1. Kishimoto TK, Viswanathan K, Ganguly T, et al.
Contaminated heparin associated with adverse clinical
events and activation of the contact system. N Engl J Med.
2008;358:2457-67.
D r. K e y i s a m e m b e r o f a n a d v i s o r y c o m m i t t e e a t
Baxter Healthcare.
BLOOD NOW ACCEPTS
ELECTRONIC CTA S AND COI FORMS
In March 2008, Blood star ted accepting electronic
copyright transfer agreements (CTAs) from authors of
papers published in the journal. By implementing electronic CTAs, Blood has eliminated paper processing
and fax transmission of forms and documents. The
Blood submission and peer-review process is now
entirely electronic.
How the Process Works
The process works as follows:
• The corresponding author is required to provide
valid e-mail addresses for all authors upon submission. Authors are notified of submission.
• Each author is required to double-click (i.e., confirm) their acceptance of the transfer. An “I agree”
response is equivalent to signature and copyright
transfer to ASH.
• Staff can track the progress or upload a PDF of a
hard copy of the form. Other wise, the staff is not
able to fill out or alter the form on behalf of an
author.
The Advantages
Although this new process may slightly extend the
time from acceptance to prepublication in First
Edition for authors who are nonresponsive, electronic
CTA submission offers these advantages:
• Preempts possible authorship disputes by informing
all authors via an automatic e-mail message at submission and at acceptance that a submission to
Blood with their name has been made. It notifies all
authors of the authorship order.
• Eliminates sending the CTA and COI form via fax
and the need to maintain the paper records in perpetuity.
• Keeps all records in electronic format. Paper forms
can be scanned and added to the system.
• Potentially speeds up the process of receiving the
signed forms.
For more information, see the Blood Author Guide at
http://bloodjournal.hematologylibrary.org/authors/
authorguide.dtl.
4
P R A C T I C I N G
H E M A T O L O G I S T
ASK THE HEMATOLOGIST:
TREATING A 61-YEAR-OLD MAN
WITH RECENT-ONSET ATRIAL FIBRILLATION
CRAIG KESSLER, MD
Dr. Kessler is Professor of Medicine and Director of the Coagulation Laboratory at
Georgetown University.
I recently received the following question from an ASH member through the Society ’s
Consult-a-Colleague program. He asked:
I have a patient with mild hemophilia and a factor VIII level of 21 percent. He is 61 years
old. He has recent-onset atrial fibrillation. I have recommended acetylsalicylic acid (ASA)
since he has basically lone atrial fibrillation and no evidence of any cardiac disease. I also recommended the possibility of doing a transesophageal echocardiogram and, if negative, cardioverting him without anticoagulation. He has bled with surger y in the past but never otherwise. Do you agree with these recommendations?
THE RESPONSE
I agree with this approach in this patient in the context of mild hemophilia A (factor VIII
level of 21 percent of normal); however, my recommendations are empirical and are derived
from my own experience, since these clinical situations are too unusual to develop evidencebased guidelines. In addition, the approach to mild hemophilia A is going to be somewhat less
challenging than what would be required with severe hemophilia A. In any case, a factor VIII
level of 21 percent should be adequate to sustain the anti-platelet aggregation effects of ASA
(81 mg daily).
The fundamental question here is whether aspirin is an effective single agent to prevent the
cardioembolic complications of atrial fibrillation. Recent large clinical trials and meta-analyses
provide some insights. War farin appears to be superior to anti-platelet agents in preventing
embolic stroke in patients over the age of 75 and in those with hypertension, prosthetic heart
valves, mitral stenosis, or congestive heart failure. Others with atrial fibrillation seem to do
equally well with aspirin alone. 1 The 2007 Cochrane Report on this topic analyzed data from
eight trials including more than 9,500 non-coagulopathic individuals (mean age = 69 years)
with non-valvular atrial fibrillation. 2 There were mixed statistical messages delivered in this
publication in that while warfarin reduced the risk of all strokes by 32 percent compared with
aspirin (P=0.0007) and decreased the incidence of disabling or fatal stroke by 31 percent
(P=0.06), the mortality rate in both groups was similar. Of note, warfarin increased the risk
of intracranial hemorrhage by 98 percent compared with aspirin. This latter risk issue has particular relevance for an individual with hemophilia, since it is ver y likely that any intracranial
bleed (warfarin- or aspirin-induced) would result in exaggerated morbidity and mortality.
For the patient at hand with mild hemophilia A, I would place him on aspirin (81 mg daily)
and would avoid warfarin until or unless an embolic event occurs or unless it is determined
that there is a mitigating circumstance contributing to the onset of atrial fibrillation (e.g.,
valvular disease, cardiac disease, etc.). I would not expect any significant aspirin-induced
hemorrhagic events to occur at this level of factor VIII activity. If the patient has severe or
moderate-severity hemophilia A (FVIII <5 percent), I would recommend the same aspirin
dose, initiate a secondar y prophylaxis regimen of FVIII replacement therapy with a recombinant factor VIII concentrate (25-30 IU/Kg three times weekly), maintain the trough FVIII
level greater than 5 to 10 percent, and subsequently titrate the dose of FVIII concentrate to
achieve a FVIII activity adequate to minimize the development of spontaneous bleeding complications. If warfarin is needed in the context of hemophilia, I would aim for a target INR of
2 to 2.5 and administer once or twice daily FVIII concentrate to maintain FVIII levels of
>50 percent, titrated upward based on the propensity of the patient to experience bleeding
complications.
As for cardioversion, I would replace this patient’s factor VIII activity level to at least 50 percent of normal with recombinant factor VIII concentrate prior to the procedure and then proceed with cardioversion without concurrent anticoagulation. Lastly, I think that this patient
should be screened for the von Willebrand disease (VWD) variant 2 Normandy, since a number of patients with mild cases of hemophilia have been shown to be phenotypically similar to
and genotypically confirmed to actually have this VWD variant. 3
1. Fuster V, Rydén LE, Cannom DS, et al. J Am Coll Cardiol. 2006;48:854-906.
2. Aquilar MI, Hart R, Pearce LA. Cochrane Database Syst Rev. 2007; Cochrane Database
Syst Rev. 2007; 3:CD006186.
3. Tuley EA, Gaucher C, Jorieux S, et al. Proc Natl Acad Sci USA.1991;88:6377-81.
The Society’s Consult-a-Colleague program facilitates the exchange of clinically
focused information between ASH colleagues. ASH members can submit questions
through the ASH Web site that are related to any of the following disease areas
(both adult and pediatric): hemostasis/thrombosis, leukemia, lymphoma, and
myeloma. Participants will receive a response from a colleague within one to two
business days. Starting in August, the program is being expanded to accommodate
requests related to Waldenström macroglobulinemia.
To take advantage of this member benefit, go to www.hematology.org/policy/
resources/consult.cfm.
The Hematologist: ASH NEWS AND REPORTS
M I N I
R E V I E W
Mouse Models of Leukemia: Pros and Cons
BENJAMIN S. BRAUN, MD, PhD; SCOTT W. LOWE, PhD; KEVIN SHANNON, MD
Dr. Braun is Assistant Adjunct Professor at the University of California, San Francisco.
Dr. Lowe is a Howard Hughes Medical Institute Investigator, and Professor in the Watson School of Biological Sciences and Deputy Director of the
Cancer Center at Cold Spring Harbor Laboratory.
Dr. Shannon is Roma and Marvin Auerback Distinguished Professor of Pediatric Molecular Oncology at the University of California, San Francisco.
any hematologic malignancies remain lethal
despite intense research that has uncovered
many of the underlying molecular lesions.
Below we address the role of mouse models of cancer
in developing and testing new therapies for treating
these diseases.
M
the hypersensitivity of myeloid progenitors to GMCSF in models of human myeloproliferative disease. 6,7
In one example of applying a classic cell biology
assay to leukemia therapeutics, the therapeutic index
of imatinib mesylate was predicted by its differential
effect on myeloid progenitor colonies grown from
CML but not normal bone marrow. 8
Goals of mouse models
Model systems aim to provide robust platforms for
investigating the basic genetic and biochemical components of malignant behavior. Furthermore, mice
potentially can be used in preclinical evaluation of
novel therapies. 1,2 A common theme is the ability to
perform controlled experiments that are difficult or
impossible in humans. Unlike patients, mice can be
designed to have both a defined genotype and congenic siblings that ser ve as controls.
Design strategies
Based on the extensive molecular understanding of
human leukemias, many of these diseases have now
been modeled in mice. Several distinct methods can
be used to introduce oncogenic mutations into the
murine hematopoietic system. 3 In conventional transgenic models, an oncogene is integrated at a random
site in the genome. While these systems have proven
quite valuable, they suffer from poor control over
oncogene copy number and expression pattern due to
integration effects. Conditional gene targeting
addresses these concerns by modifying the endogenous locus of a proto-oncogene or tumor suppressor
gene and allows a mutation be induced at a specific
time and/or lineage. To date, this approach provides
the most accurate genetic model of oncogenic mutations. Finally, retroviral transduction is a rapid
method for generating series of genetically related
leukemias. In some cases, proviral insertion can be
deliberately exploited to generate leukemias by insertion mutagenesis. 4
Useful aspects of hematopoietic cancer models
Genetic diversity may be regulated: Acute leukemia in
humans or mice involves multiple cooperating mutations, but most mouse models are designed with only
one mutation in the germline. Therefore, additional
genetic changes take place during leukemic transformation. These secondar y events occur at random,
leading to some genetic diversity among the tumors.
Retroviral insertion screens have been a highly successful approach for systematically defining such
cooperating lesions. Alternatively, multiple oncogenic
mutations can be designed into the model by crossbreeding or other strategies. Leukemia development
in this setting will require fewer random mutations,
and the resulting tumors will be more similar to one
another. 5 In essence, by var ying the number of engineered oncogenic mutations, the investigator may control the degree of genetic diversity in the system.
Primary tumor cells are accessible for analysis: Once
established, murine malignancies can be har vested
and subjected to biochemical or genomic analysis.
The high proportion of malignant cells in target
organs results in nearly pure populations for study,
although subfractionation can be performed if
desired. Tumors may be queried for secondar y genetic
mutations, proliferative activity, and, importantly, the
inhibition of the molecular target of therapeutic
agents in the target cell population. 9,10
Transplantability: Hematopoietic malignancies are
almost always transplantable into naïve hosts. The
reproducibility of engrafted tumors facilitates performing controlled, replicated experiments to examine
responses to therapeutic inter vention in vivo. The
system is easily scaled up, making complex comparisons of multiple strains and treatment regimens feasible.
Genetic manipulation of primary tumor cells:
Retroviral transduction of primar y leukemia cells can
produce a series of tumors with related genetic alterations. By var ying both transduced genes and the
genetic background of transduced cells, genetic contributions to disease and response to therapy can be
analyzed efficiently. The ability to simultaneously
produce large numbers of recipients with defined
mutations in the hematopoietic compartment allows
such hypotheses to be tested more quickly at a fraction of the cost and complexity involved in mating
mouse strains. 11,12 Recent advances in RNA interference technology have extended this approach to
inhibiting target gene expression.
Clear disease endpoints: Besides sur vival, intermediate endpoints of clinical appearance, peripheral blood
counts, and/or lymphadenopathy are robust measures
of efficacy in preclinical therapeutic studies.
Noninvasive imaging systems can also quantify tumor
burden over time if cells are marked with appropriate
reporter genes. These measures collectively establish
a basis for comparing disease progression in treatment studies. The clarity of these endpoints lends
considerable power to statistical analysis, allowing
small trials to yield meaningful results.
The ease of quickly generating large cohorts of diseased animals, combined with the statistical power of
small but uniform samples, is especially valuable
when evaluating a large number of potential therapies. Therefore, mice may prove particularly helpful
when novel agents are tested in combination.
The Hematologist: ASH NEWS AND REPORTS
Pharmacology: A second concern relates to the
mouse host, regardless of how accurately the tumor is
modeled. Potential differences in pharmacology or
toxicology can affect the interpretation of therapy trials, which depend on finding anti-tumor effect at a
nontoxic dose. A notorious example involves investigations of camptothecins, which have vastly different
pharmacology in mice and humans. 13
Alternatives: Some translational researchers prefer
xenograft models, in which human tumors are engrafted into mice. These have one potential advantage —
they use actual human cancer cells. However, these
systems lack the power of genetic systems applicable
to mice and suffer from the same potential pharmacologic problems. Lastly, immortalized cell lines have
revealed important facets of biochemistr y and molecular biology, but are less useful for discovering more
subtle and complex effects that are restricted to primar y cells. Studies of drug sensitivity in cell lines are
relatively fast, cheap, and easy, but experience has
shown that they do not necessarily provide lasting
value.
Will they work?
Will the increasing sophistication of mouse cancer
models yield systems with enough predictive value
and throughput to identify effective treatments for
human diseases? Experience with models of acute
promyelocytic leukemia (APL) is particularly encouraging. First, leukemias in PML-RARA transgenic
mice were found to respond to all-trans-retinoic acid
(ATRA) and arsenic trioxide (As 2 O 3 ) with differentiation and apoptosis, as had already been seen in
pioneering human clinical trials. 14,15 In this sense, the
patients correctly predicted outcomes in the mice.
Later, the model systems predicted a synergistic interaction between ATRA and As 2 O 3 , an effect only
recently validated in the clinic. 16 New predictions that
cAMP agonists also cooperate with ATRA will soon
be tested in patients. 17 Perhaps the mouse models will
soon replace traditional Chinese medicine as the
inspiration for novel therapeutic approaches in APL
and other leukemias.
1. Singh M, Johnson L. Clin Cancer Res. 2006;12:5312-28.
2. Olive KP, Tuveson DA. Clin Cancer Res. 2006;12:5277-87.
3. Frese KK, Tuveson DA. Nat Rev Cancer. 2007;7:645-58.
4. Neil JC, Cameron ER. Cancer Cell. 2002;2:253-5.
5. Mikkers H, et al. Nat Genet. 2002;32:153-9.
6. Lavau C, et al. Embo J. 1997;16:4226-37.
Potential weaknesses
Well-established cell biology assays: Decades of
research into basic mechanisms of hematopoiesis have
revealed extensive similarities between human and
murine hematopoiesis and have yielded a large set of
techniques to assess cell biology in normal and diseased states. As a result, the effects of an oncogenic
mutation on cell fate can be determined with some
clarity. For example, traditional colony-formation
assays readily demonstrate the enhanced self-renewal
imparted by some oncogenic transcription factors and
of genetically identical cells, failing to model the
important process of clonal selection. Finally, whereas
many mouse cancer models rely upon engineering a
specific mutation into the germline, it is not always
certain that these mutations represent bona fide initiating events in human hematologic cancers.
Discordant results between mouse preclinical studies
and human trials may reflect the fact that a specific
mutation that initiates leukemogenesis in the mouse
may not play the same role in human disease.
Inaccuracies: There are three fundamental ways in
which mice can model human disease poorly. First,
the engineered genetic lesions can only approximate
those found in patient samples. Some conditional
models come ver y close, but most are imperfect in
some way. A second type of inaccuracy results from
the inability to ensure that a single cell of the proper
type undergoes the initiating oncogenic mutation. In
most systems, the mutation occurs in a large “field”
7. Bollag G, et al. Nat Genet. 1996;12:144-8.
8. Druker BJ, et al. Nat Med. 1996;2:561-6.
9. Wendel HG, et al. Nature. 2004;428:332-7.
10. Van Meter ME, et al. Blood. 2007;109:3945-52.
11. Schmitt CA, et al. Cancer Cell. 2002;1:289-98.
12. Li S, et al. J Exp Med. 1999;189:1399-412.
13. Erickson-Miller CL, et al. Cancer Chemother Pharmacol. 1997;39:467-72.
14. Rego EM, et al. Proc Natl Acad Sci USA. 2000;97:10173-8.
15. Lallemand-Breitenbach V, et al. J Exp Med. 1999;189:1043-52.
16. Shen ZX, et al. Proc Natl Acad Sci USA. 2004;101:5328-35.
17. Guillemin MC, et al. J Exp Med. 2002;196:1373-80.
5
N E W S
A N D
R E P O R T S
NHLBI REALIGNS SICKLE CELL DISEASE
RESEARCH PROGRAM
SUSAN B. SHURIN, MD
Dr. Shurin is Deputy Director of the National Heart, Lung, and Blood Institute.
n May 16, 1972, Congress passed the National Sickle Cell Anemia Control
Act (PL 92-294). This Act called for a national diagnosis, control, treatment, and research program to be implemented by the Department of
Health, Education, and Welfare (now known as the Department of Health and
Human Ser vices [HHS]). Its implementation was assigned to the National Heart
and Lung Institute, which established Centers to conduct research and provide education and ser vices to people with sickle cell disease (SCD). At the time, many people born with SCD died in childhood and many more in young adulthood.
O
Biomedical research and health-care deliver y has been transformed over the past 36
years. The costs of health-care deliver y have increased exponentially. Health-care
disparities remain, and in some areas have increased. Most people born with SCD
now live well into middle age and older, with substantial burden of disease experienced by them and their families, who often have serious problems accessing quality
health care. The findings of a recent NIH Consensus Development Conference on
Hydroxyurea Treatment for Sickle Cell Disease 1 underscores the problems of ensuring that all who may benefit have access to research advances.
In this setting, NHLBI felt that it was appropriate to analyze its portfolio in SCD
to assess the effectiveness of its investment in achieving its goals and identify areas
in which adjustments should be made to funding mechanisms. We examined the histor y of investments and advances, solicited comments and suggestions from multiple
constituencies, including ASH, 2 and asked a subcommittee of our Advisor y Council
to provide an objective summar y with recommendations. The report of the
committee 3 was adopted by the full Advisor y Council at its Februar y 13, 2008,
meeting. 4
In response to the findings and the wisdom of the community, we have implemented
significant changes in our approach to SCD research. 5 We have reconfigured the
Centers to form a Basic and Translational Research Program in SCD, which will
undergo further modifications as the full research agenda evolves. We expect to
address an aggressive basic science agenda, designed to bring investigators in disciplines who have not previously been involved in SCD research into the field, to
ensure that scientific approaches not yet brought to bear can enhance the research
agenda, and to create the “Manhattan project” for SCD research recommended by
the ASH workshop. We plan to create new mechanisms for translational clinical
research, which will require that the investigator community rigorously establish priorities, and we will invite all capable investigators and patients who wish to participate in research to do so. We will enhance our support of training and career development, including broadening the specialties involved in such activities. We will collaborate with the Clinical and Translational Science Award (CTSA) Consortium to
both conduct clinical research and support training of investigators. We will involve
multiple constituencies in the development of practice guidelines and educational
materials for professionals, advocacy groups, patients, and families.
We are now actively engaged in discussions across HHS to support the missions of
our sister agencies, including sur veillance and assessment of public health needs by
Centers for Disease Control and Prevention and Health Resources and Ser vices
Administration’s goal of ensuring access to care for the medically vulnerable and
those affected by health disparities. The NIH missions are research and education.
The Institute is not positioned to implement changes in medical practice, and is thus
heavily dependent upon partnerships with payors and providers to address these
issues. We will both repurpose existing funds and partner extensively to achieve our
ultimate goals, which are to realize the promise of inter vention in the prototypical
molecular disease and to prolong and enhance the quality of life for patients with
SCD. ASH members and leadership are an integral part of implementation; we all
have a lot of work to do!
6
1.
National Institutes of Health. Panel Finds Hydroxyurea Treatment Is Underutilized for Sickle
Cell Disease. www.nih.gov/news/health/feb2008/od-27.htm. Accessed May 21, 2008.
2.
American Society of Hematology. Toward a New Research Paradigm: Building A New Sickle
Cell Disease Research Agenda. www.hematology.org/policy/statements/01092008.cfm. Accessed
May 21, 2008.
3.
National Heart, Lung, and Blood Institute. Report of the National Heart, Lung, and Blood
Advisor y Council Subcommittee Review of the NHLBI Sickle Cell Disease Program.
www.nhlbi.nih.gov/resources/docs/scd_program.htm. Accessed May 21, 2008.
4.
National Heart, Lung, and Blood Institute. Brief summar y of the Februar y 13, 2008, meeting of
the National Heart, Lung, and Blood Advisor y Council.
www.nhlbi.nih.gov/meetings/nhlbac/feb08sum.htm. Accessed May 21, 2008.
5.
National Heart, Lung, and Blood Institute. NHLBI Announcement: Institute to Realign its
Sickle Cell Disease Research Program. www.nhlbi.nih.gov/meetings/workshops/Sickle-CellAnnouncement.htm. Accessed May 21, 2008.
President Bush Signs Genetic Nondiscrimination
Legislation into Law
On May 22, President Bush signed into law the Genetic Information
Nondiscrimination Act (GINA), which prohibits discrimination based on
the results of genetic tests. Under the bill, employers cannot make decisions about whether to hire potential employees or fire or promote
employees based on the results of genetic tests. In addition, health insurers cannot deny coverage to potential members or charge higher premiums
to members because of genetic test results. The House voted 414-1 to
approve the bill, while the Senate approved the legislation 95-0. ASH
has supported this legislation for several years and thanks all members
who joined the Society ’s advocacy campaigns.
ASH Committee on Practice Meets With Congress to
Urge Support of Physician Payment Fix
The ASH Committee on Practice met with nearly 30 Congressional
offices during its spring meeting to urge Congress to prevent the scheduled 10.6 percent cut in Medicare physician payments scheduled to go
into effect July 1, 2008, and replace the cut with a positive update for 18
months. In addition, the ASH members asked for support of a permanent replacement of the formula currently used to calculate physician
payment rates. As this issue of The Hematologist was going to press,
Congress had not yet taken action on this important legislation. To
receive the most up-to-date information about this issue, please visit the
ASH Web site at www.hematology.org.
NIDDK Announces September Workshop on
Erythropoietin Expression and Function in NonHematopoietic Tissues
The Hematology Program at NIDDK is planning a two-day workshop on
er ythropoietin receptor (EpoR) expression and function in nonhematopoietic tissues. This workshop will take place on September 8-9,
2008, at the Doubletree Bethesda Hotel Meeting Center, Bethesda, MD,
and will address evolving insights into the distribution and function of
EpoR in non-hematopoietic tissues. The workshop will summarize clinical obser vations of non-hematopoietic er ythropoietin (Epo) effects in
patients with renal failure and solid tumors, and it will review experimental and clinical findings of Epo effects on the development, growth, and
function of vascular endothelial cells, neoplasias, and cardiovascular and
neural tissues. This workshop is designed to promote interactions and
discussion among workshop participants and to define key unanswered
questions and highlight priorities and directions for future research. The
program will include presentations by both invited speakers and speakers
selected from submitted abstracts, together with poster presentations.
A limited number of travel grants will be made available to registrants
whose abstracts are selected for oral presentations at the workshop.
Registrants who submit abstracts for presentation at the workshop will be
given preference if the number of registrants exceeds available space.
Registration information is available at www3.niddk.nih.gov/fund/other/
eporeceptor2008/. Individuals who wish to attend this workshop are also
invited to contact Amy Amerson of The Scientific Consulting Group at
301-670-4990, or e-mail her at [email protected].
CDC Appoints New Director for the Division of Blood
Disorders
Dr. Hani Atrash, an obstetrician/gynecologist with training in epidemiology and preventive medicine, has been appointed Director of the Division
of Blood Disorders (DBD) in the National Center on Birth Defects and
Developmental Disabilities (NCBDDD). Dr. Atrash has worked at the
Centers for Disease Control & Prevention (CDC) since 1979. In 2001,
he joined NCBDDD as an Associate Director for Program Development,
where he managed activities related to global health, workforce development, women’s health, relationships with national organizations and state
and local health departments, and minority health. Dr. Atrash is also an
accomplished scientist and prolific writer. He ser ves on a variety of key
national advisor y committees. Dr. Atrash has received numerous honors
and awards within CDC and at the national level for his work in improving the health of mothers and children. He replaces Dr. Roshni
Kulkarni, who is returning to Michigan State University.
The Hematologist: ASH NEWS AND REPORTS
T H E
I N T E R N A T I O N A L
H E M A T O L O G I S T
ASH: A GLOBAL SOCIETY
s the world’s premier professional
association representing hematologists,
ASH has grown substantially in its international
influence and impact
around the globe.
International membership
continues to expand,
international professional
attendance at the ASH
annual meeting hovers
around 50 percent, and
ASH continually seeks
means of increasing the
scope and breadth of programs targeted toward
international hematologists.
A
GROWTH IN
I N T E R N AT I O N A L M E M B E R S
the globe, although
abstracts submitted by nonmembers must be sponsored by an ASH member.
MY TH :
3,729
I cannot participate in Blood’s publication
process.
3,529
To meet the unique needs in research,
practice, and training of hematologists
in developing countries, ASH offers a
spectrum of programs.
3,401
FACT : International hematologists may participate in
ever y stage of the publica2,941
tion process for Blood,
including reviewing manuscripts, ser ving on the editorial board, and authoring
articles; in fact, more than
2006
2005
2004
2008
2007
half of submitted papers
come from outside North
America. Read the article,
“International Blood,”
Hematologists outside of
written by Blood Editor-inNorth America may be
Chief Cynthia Dunbar,
elected to International membership upon the recomMD, in the May/June issue of The Hematologist to
mendation of the Executive Committee. These memlearn more about the process for editorial board
bers represent roughly a quarter of the Society ’s total
appointments and tips on how to get published in the
membership and have the same privileges as Active
journal. Go to www.hematology.org/publications/
members, except the rights to vote and hold office. To
hematologist/MJ08/hem_international.cfm to read the
begin membership in Januar y 2009, applications must article online.
be received by August 1, 2008.
MY TH : ASH never recognizes International members
Benefits of International membership include:
for career-achievement awards.
3,194
• A subscription to Blood: Journal of the
American Society of Hematology
• All annual meeting mailings in advance
• Reduced registration rates and priority hotel
reser vations at the annual meeting
• Eligibility to sponsor abstracts
• Access to Consult a Colleague, an online ser vice
to submit clinical questions to respected colleagues in specific areas of hematology
• Society publications and the membership director y
Below are some misconceptions about international
membership and the opportunities available to international members.
MY TH :
I N T E R N AT I O N A L
OUTREACH PROGRAMS
FACT : International hematologists are eligible to
receive several career-achievement awards, including
the Ham-Wasserman Lecture, which is traditionally
awarded to an individual from outside of the United
States; the William Dameshek Prize; the Henr y M.
Stratton Medal; the E. Donnall Thomas Lecture and
Prize; the Mentor Award; and the Wallace H.
Coulter Award for Lifetime Achievement in
Hematology. International hematologists are also eligible for career-development awards; in particular,
European hematologists are eligible for the EHAASH International Fellowship Award. The ASH
Web site contains descriptions of each of these
awards, including eligibility criteria and
application/nomination deadlines.
• The Visiting Trainee Program provides
short-term funding to individual hematologists who seek specific clinical
laboratory or technological training at
a host institution under the mentorship of an ASH member. During this
period, the participants will gain new
knowledge and skills that can be
applied upon returning to their home
institutions.
• Through the International Outreach
Initiative, hematology-related institutions can receive ASH educational
materials free of charge, including a
subscription to Blood, annual meeting
materials, and materials from small
meetings.
• The International Consortium on
Acute Promyelocytic Leukemia (ICAPL) fosters interactions between clinicians and researchers with the
goals of improving clinical care and
creating the infrastructure for ongoing clinical trials and translational
research.
• ASH recently partnered with Health
Volunteers Overseas (HVO) to recruit
ASH members to teach basic hematology in the most impoverished areas
of the world. Recruitment has begun
for sites in Kampala, Uganda, and
Siem Reap, Cambodia; more sites in
Asia and Latin America are anticipated.
Fur ther information on ASH’s outreach
programs in developing countries is
available online.
MY TH :
I am not eligible to ser ve on an ASH commit-
Travel support to attend the ASH Annual
Meeting is unavailable to international members.
tee.
FACT : International members may become members of
ASH standing and scientific committees. Currently,
international members ser ve on four standing and 12
scientific committees.
They are represented in the leadership of the Society
by the International Members Committee, which
advises the Executive Committee about issues relevant
to international hematologists and makes recommendations to the Nominating Committee about international representation in the Society ’s leadership and
potential committee members. IMC membership is
restricted to members from outside of North America.
As a volunteer-run association, self-nomination for
committee ser vice is encouraged and welcomed as a
good indication of interest in leading the Society.
MY TH :
As an international member, I cannot submit
an abstract to the annual meeting.
FACT : Abstracts are accepted from ever y corner of
The Hematologist: ASH NEWS AND REPORTS
FACT : To help defray annual meeting expenses, ASH
offers need- and merit-based travel awards to trainees.
Trainees presenting an abstract at the ASH annual
meeting and demonstrating financial need may receive
a $500 travel award. (You do not have to be a member of ASH to receive these travel awards.)
Presenters with the highest scoring abstracts in the
categories of undergraduate student, medical student,
graduate student, resident physician, and post-doctoral fellow (MD or PhD) may receive travel reimbursement in addition to the $500 honorarium. Application
deadlines for these awards coincide with the abstract
submission deadline.
ASH continues to fulfill its mission to help hematologists worldwide conquer blood diseases. The array of
benefits, awards, and programs available to international hematologists furthers the understanding of
hematology globally through international collaboration, fosters the worldwide exchange of knowledge and
resources, and enhances clinical care through education and training.
I M P O R TA N T D AT E S
August 1, 2008: To begin membership
in January 2009, applications must be
received by this date. Annual dues for
International members are $245.
August 21, 2008: Abstracts must be
submitted by this date to be considered
for the annual meeting.
August 21, 2008: Application deadline
for trainees who seek need- and meritbased travel awards.
7
Optimism and Caution on the Use of MSCs in Patients Undergoing HSCT for Hematologic Malignancies
Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.
Lancet. 2008;371:1579-86.
Ning H, Yang F, Jiang M, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic
malignancy patients: outcome of a pilot clinical study. Leukemia. 2008;22:593-9.
esenchymal stem (or stromal) cells (MSCs) are culture-derived,
non-hematopoietic, adherent progenitors that are defined by
specific immunophenotypic features and the ability to differentiate into adipocytes, chondrocytes, or osteoblasts. In vivo, MSCs can
migrate to sites of tissue injury and inflammation where they produce
trophic and growth factors that facilitate repair and regeneration.
MSCs also suppor t hematopoiesis; they are relatively non-immunogenic
and can down-modulate T-cell-mediated alloreactivity. 1 Pilot and phase II
studies in allogeneic hematopoietic stem cell transplantation (HSCT)
suggest that donor or mismatched, “third par ty,” marrow-derived MSCs
are safe and can enhance engraftment in cer tain patients or treat corticosteroid-refractory graft-versus-host disease (GVHD). Impor tantly,
MSCs are also recruited to tumor microenvironments, and studies in
murine or human xenograft tumor models show that systemic delivery
or co-implantation of MSCs can promote malignant cell sur vival, proliferation, and/or metastasis. 2-4 Thus, the safety of MSCs in patients
undergoing HSCT for malignancies remains a major concern.
M
The repor t by LeBlanc, et al. describes a multicenter, non-randomized
phase II trial of donor or third-par ty marrow MSCs for severe, steroidrefractory acute GVHD after myeloablative or non-myeloablative HSCT
for a hematologic malignancy (78 percent), solid tumor (4 percent), or
non-malignant disease (12 percent). One intravenous infusion of MSCs
induced a complete response (CR) in 27 of 55 patients (49 percent),
and CR occurred in 30 patients overall (55 percent). Compared with
patients without CR, those with CR had significantly lower one-year
transplant-related mor tality (37 percent vs. 72 percent) and higher
two-year sur vival (53 percent vs. 16 percent). Response was not related to GVHD grade, MSC source, or total MSC dose. No acute or late
side effects were repor ted; relapse occurred in three of 43 patients
(7 percent) with hematologic malignancy. In the randomized controlled
trial by Ning, et al., HLA-matched donor MSCs were co-transplanted
with marrow and/or peripheral blood stem cells on day zero after myeloablative conditioning for hematologic malignancies. Patients were randomized by age, disease type, stage, and prognosis. Only 10 of 15
patients allocated to the treatment arm received MSCs; their engraftment was not enhanced, but only one developed GVHD, compared with
eight of 15 non-MSC control patients. The study was closed early
because six of the 10 patients who received MSCs relapsed (including
Figure
Migrate to sites of tissue injury and inflammation;
facilitate repair and regeneration
five recurrences by day 150), compared with three relapses in the 15
non-MSC patients. The three-year disease-free sur vival rates for the
MSC and non-MSC groups were 30 percent and 66.7 percent, respectively (log rank p=0.035).
These obser vations add to the growing experience of using cultureexpanded MSCs in HSCT. The results of LeBlanc, et al. are highly
encouraging. If confirmed in current randomized clinical trials, MSCs
could offer the safest and most effective salvage therapy option for
steroid-resistant acute GVHD. This enthusiasm must be tempered,
however, by the obser vations of Ning, et al. that remind us that MSCs
can promote malignant cell sur vival and growth. Reassuringly, high
relapse rates were not obser ved in a similar, but non-randomized,
study of 46 patients with hematologic malignancies undergoing myeloablative HSCT with MSC co-transplantation on day zero, 5 nor have
increased relapse rates been repor ted after administering MSCs for
GVHD. Moreover, the results of Ning, et al. may not be broadly applicable because their study groups were small and the technical limitations
that prevented optimal donor MSC expansion could have introduced
confounding variables. Additional clinical and pathobiological studies
are needed to address whether MSCs enhance disease recurrence
after HSCT, especially when co-transplanted on day zero, and if this
might occur through direct cell-cell interactions, paracrine effects,
and/or suppression of graft-versus-tumor alloreactivity.
1. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression
occurs via concer ted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:14150.
2. Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells
favors tumor growth in allogeneic animals. Blood. 2003;102:3837-44.
3. Ramasamy R, Lam EW, Soeiro I, et al. Mesenchymal stem cells inhibit proliferation and
apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia. 2007;21:304-10.
4. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557-63.
5. Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling cultureexpanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy
patients. Biol Blood Marrow Transplant. 2005;11:389-98.
Down-modulate T-cell-mediated alloreactivity;
suppress clinical graft-versus-host disease
MSCs
Recruited to tumor micro-environments;
promote malignant cell survival, proliferation, and metastasis
Support hematopoiesis; enhance engraftment
after hematopoietic stem cell transplantation
Culture-derived MSCs, which are defined by specific immunophenotypic features and their ability to differentiate into adipocytes,
chondrocytes, or osteoblasts in vitro, exhibit pleiotropic functions in vivo.
MICHAEL LINENBERGER, MD, FACP
Dr. Linenberger indicated no relevant conflicts of interest.
8
The Hematologist: ASH NEWS AND REPORTS
Gene Dosage and Lineage Commitment in Myeloid Leukemia
Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood.
2008;111:3931-40.
utations in tyrosine kinases are a common theme in myeloid leukemia. The hallmark example
is the inappropriate activation of Abl through the Bcr-Abl translocation in CML. Mutations in
the FLT3 tyrosine kinase are quite common in AML. Recently, point mutations resulting in a
valine to phenylalanine substitution at amino acid 617 of the JAK2 kinase (JAK2-V617F) have been
found in >90 percent of cases of polycythemia vera (PV), and approximately 50 percent of primary
myeloid fibrosis (PMF) and essential thrombocytosis (ET). How can one mutation be associated with
three different diseases?
M
Figure
A)
A recent study by Tiedt, et al. paints a fascinating picture of how the mutant gene level can actually
influence the malignant phenotype. The authors used elegant genetic engineering to create three
mouse models: one with a balanced expression of the wild-type JAK2 and mutant JAK2-V617F, one
with relatively high JAK2-V617F, and one with very high JAK2-V617F. The mice developed a hematologic disease influenced by the relative amount of wild-type to mutant allele. Thus, mice expressing
balanced expression of wild-type and mutant Jak2 developed an ET-like disease, with increases predominately in platelet counts, splenomegaly, and fibrosis in the bone marrow. Mice that expressed
higher levels of mutant JAK2-V617F showed increasing levels of erythroid expansion, with a phenotype that appeared PV-like. A study of 82 patients with myeloproliferative disease and 11 healthy
people showed a similar pattern as the mouse model. Quantitative RT-PCR showed the highest
mutant: wild-type ratio in cases with PV, followed by PMF, then ET. Expression of the mutant and
wild-type JAK2 correlated with the gene copy numbers found in the samples. Thus, cases with PV
tended to have samples where the chromosomal number of mutant JAK2 was greater than wild-type.
A variation of this theme has been found in AML cases with the FLT3 mutation. Approximately 15
percent to 30 percent of AML cases with normal cytogenetics harbor FLT3 mutations characterized
by a head-to-tail duplication in gene coding for the juxtamembrane region of the protein. The occurrence of this FLT3 internal tandem duplication (FLT3-ITD) alone has had a variable prognostic impor t
across different studies and treatments. However, several studies have now shown that the allelic
ratio (the ratio of mutant FLT3-ITD to wild-type allele) drives prognosis. 1-3 Cases with predominately
mutant FLT3-ITD have a very poor prognosis; cases with predominately wild-type allele tend not to
have a poor prognosis.
Allele A
Allele B
ITD
B)
X
X
C)
These findings run counter to the conventional (and, perhaps, wrong) wisdom of leukemia being a
single clonal event. If AML really is only derived from a single clone, there could only be three possible allelic ratios in respect to the FLT3 mutation in an AML sample: all wild-type; heterogyzgous wildtype and mutant; or all mutant. The fact that one can have a variety of allelic ratios in AML cases
suggests that there must be multiple clones in most leukemic cases, each clone having a different
state of the three conditions outlined above.
Of interest, the allelic data suggest not only the case of a loss of the normal FLT3 (resulting in one
mutant gene, no wild-type), but in some cases, a duplication of the mutant gene. How does a patient
develop two copies of a mutant gene? Bad luck twice? In some cases of malignancy, wild-type alleles
are dropped through chromosome loss (for example, deletion of an arm of chromosome 17 eliminates a copy of the p53 tumor suppressor gene). This loss of heterozygosity, however, does not
appear to be the case in the JAK2 and FLT3 story. Here, rather, the process of chromosomal repair
causes a duplication of the mutant allele (see Figure). In this situation, a double-stranded DNA break
takes place, and, in order to facilitate repair, a second copy of one of the genes is made. In the
process of repair, one of the copies of the genes is lost. If the recombination process selects the
wild-type gene to duplicate, then the cell has two copies of the wild-type gene, and order is restored.
If, in this process, the wild-type gene is selected, then the cell has two copies of the mutated gene.
Thus, the mere presence of a mutated tyrosine kinase does not tell the whole story in myeloid malignancies. The dosage level of the mutated gene can affect the disease phenotype and the biology of
response. Once again in science and medicine, the more we know, the more we need to know.
An example of DNA repair causing a
duplication of a mutated gene.
A)
The normal state with two
wild-type alleles.
B)
The acquisition of a mutated
sequence (green) leaves the
gene in a heterozygous
state.
C)
In the process of repair, a
copy of the mutated gene is
created and spliced into the
other chromosome, leaving
two copies of the mutated
gene sequence.
1. Whitman SP, Archer KJ, Feng L, et al. Cancer Res. 2001;61:7233-9.
2. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Blood. 2006;108:3654-61.
3. Gale RE, Green C, Allen C, et al. Blood. 2008;111:2776-84.
JERALD RADICH, MD
Dr. Radich indicated no relevant conflicts of interest.
The Hematologist: ASH NEWS AND REPORTS
9
Reworking Our Textbooks
Epidermal Sensing of Oxygen Regulates Systemic Hypoxic
Response
Wada H, Masuda K, Satoh R, et al. Adult T-cell progenitors
retain myeloid potential. Nature. 2008;452:768-72.
Boutin AT, Weidemann A, Fu Z, et al. Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell. 2008;133:223-34.
Bell JJ, Bhandoola A. The earliest thymic progenitors for T cells
possess myeloid lineage potential. Nature. 2008;452:764-7.
ho’s your daddy? This seems like a simple question, but in hematopoiesis the answer may not be
so simple. We all know that blood is made up of
red cells, white cells, and platelets. They all are derived
from a hematopoietic stem cell. The red cells and platelets
are derived from a common precursor. White blood cells, on
the other hand, come in many different flavors with a very
specialized function. They also seem to segregate broadly
into differentiated myeloid and lymphoid cells through a
series of less well-understood intermediates. The bifurcation
or restricted commitment of these two lineages is thought
to occur early on in differentiation. The myeloid lineages are
derived from a common myeloid progenitor (CMP), and the
lymphocytes are derived from a common lymphoid progenitor
(CLP). This picture came from the description of the CLP,
which was able to give rise to T, B, and NK cells but not to
myeloid cells. The car toon is well entrenched in our thinking
of hematopoietic development and in every slide set of
hematopoiesis.
W
But, is it correct? Two recent publications have challenged
this dogma and provide definitive data that the picture is not
so cut-and-dried. Before delving into the data, a very brief
review of thymopoiesis is needed. While all the other blood
elements mature in the marrow spaces, T-cell development
is thought to proceed from a CLP that migrates from the
bone marrow to the thymus where a tightly orchestrated set
of events results in the release of a naïve T cell that has
been positively selected (to recognize the appropriate MHC
molecules) and negatively selected (to remove auto-reactive
T cells). The T-cell precursor begins as double-negative (DN)
1 (DN1 [CD44+CD25-CD117+], then DN2
(CD44+CD25+CD117+), and DN3 (CD44-CD25+), CD4/CD8
double-positive, and finally single-positive (CD4 or CD8) naïve
T cell. Based on this elegant knowledge of T-cell development, there should not be any question as to whether these
T-cell precursors could give rise to myeloid cells.
However, using clonal analysis with single-cell assays, these
two group of investigators demonstrated that a substantial
number of early T-cell precursors in the thymus at the DN1
and DN2 stage (prior to T-cell receptor rearrangement) have
myeloid potential, which is lost at the DN3 stage. These
myeloid cells were predominantly macrophages, but granulocytes and dendritic cells were also obser ved. Transfer of
DN1 cells into T-cell-deficient mice demonstrated that up to
one-third of the macrophages were derived from the T-cell
precursors. Even more surprising was that these myeloid
cells demonstrated rearrangement of the T-cell receptor and
even expressed RAG recombinase, the enzyme necessary to
create T-cell receptor diversity. Taken together, these data
demonstrate that the early T-cell precursor is not yet fully
committed to becoming only T cells.
What are the ramifications? These early T-cell precursors
could explain the origin of some leukemias, which are biphenotypic. But more impor tantly, it is clear that a progenitor’s
potential can be different from what actually occurs in vivo.
Simple characterization of such precursors may not fully
describe their potential. We do not know what the molecular
signals are in this case or whether it is similar to the need
for PAX5 expression for B-cell lineage commitment, where a
single switch may determine the fate of the cell. However,
these data go a long way in getting our lineages right.
mphibians respond to changes in environmental oxygen at least in par t
through their skin, and frogs can use their permeable skin to derive oxygen
directly from the atmosphere. Mammalian skin, however, has generally been
thought of as an impermeable barrier, with no direct communication between outside environment and inner respiratory physiology. Mammals are known to sense
changes in oxygen pressure by carotid bodies that regulate cardiovascular and
respiratory response and by the kidneys and liver that regulate erythropoiesis by
erythropoietin production. Boutin and colleagues, however, have created a series
of experiments that demonstrate unanticipated regulation of erythropoiesis by
novel regulation of renal ery thropoietin production via epidermal O 2 sensing.
A
The erythropoietin (EPO) gene is one of many “hypoxia-regulated” genes whose
expression is controlled by the master transcription factors, hypoxia-inducible factors-1 and -2 (HIF-1 and HIF-2), each composed of dimers of α and β subuni ts. O nl y
the H I F α subuni ts are regulated by hy pox i a, and thei r ex pressi on i s control l ed post-transcriptionally. Under normox i c condi ti ons, the prol y l resi dues of H I Fs are hy drox y l ated by
the enzy me prol y l hy drox y l ase, whi ch al l ows the von H i ppel - Li ndau protei n (pV H L) to
bi nd to H I F α, l eadi ng to rapi d degradati on by the ubi qui ti n- proteasome pathway. Duri ng
hy pox i c condi ti ons, H I F α i s stabi l i zed ( by not bei ng targeted for proteasome degradati on)
and forms a transcri pti onal compl ex wi th H I F β that l eads to i ncreased ex pressi on of multiple target genes i nvol ved i n di verse processes, i ncl udi ng cel l prol i ferati on and survi v al ,
metabol i sm, angi ogenesi s, and ery thropoi esi s. HIF-1 α and HIF-2 α ex hi bi t high sequence
homol ogy but have di fferent mRNA ex pressi on patterns. HIF-1 α i s ex pressed ubi qui tousl y,
whereas HIF-2 α ex pressi on i s restri cted to certai n ti ssues. Both HIF-1 α and HIF-2 α are
regul ated by i denti cal mechani sms duri ng hy pox i a and form a heterodi mer wi th the same
H I F- β subunit. HIF-1 is the principal regulator of EPO gene transcription in the kidney. In other tissues, such as brain and liver (that generates ~ 20 percent of circulating erythropoietin), EPO gene transcription is HIF-2-dependent.
Boutin and colleagues created a mouse with conditional deletion of Vhl in epidermal keratinocytes, which caused cutaneous vasodilation and increased expression
of Hif-1 α and Hif-2 α . A l though kerati nocy tes do not make ery thropoi eti n, the erythropoietin l evel was nonethel ess found to be i ncreased, and the mouse became pol y cy themi c.
Further studi es of thi s epi dermal Vhl knockout mouse revealed that the elevated levels of hif-1 caused upregulation of inducible nitric oxide synthase, which in turn led
to increased cutaneous nitric oxide (NO), a potent vasodilator. This NO-induced
skin vasodilation resulted in decreased perfusion of other organs, most notably the
liver, with subsequent hypoxia-induced, increased expression of hepatic Hif-2 α ,
whi ch i n turn caused i ncreased ex pressi on of the Epo gene. In follow-up experiments
using mice with wild-type Vhl, the authors deleted the cutaneous genes for either
Hif-1 α or Hif-2 α . Unex pectedl y, under condi ti ons of normox i a, the l oss of Hif-1 α and Hif2 α had no effect on ery thropoi eti n l evel s. Under hy pox i c condi ti ons, however, the Hif-1 α
epi dermal k nockout mi ce di d not di spl ay an appropri ate i ncrease i n renal Epo gene transcription and were unable to mount an appropriate renal erythropoietin response.
These experiments show the impor tance of epidermal hif in sensing environmental
oxygen levels and regulating systemic hypoxic responses in mice, with physiologic
regulation mediated primarily by hif-1α whi l e the pathol ogi c l oss of Vhl is mediated
primarily by hif-2 α .
Although these experiments were carried out using mice, the question of whether
these results suggest a broader role for mammalian skin in general is compelling.
While mice are not people, the par tial inhibition of VHL in humans causes Chuvash
polycythemia, 1 a condition with a complex phenotype, the pathophysiological and
molecular basis of which is not yet fully defined, but includes elevated erythropoietin levels and an increased risk of thrombosis that remains unexplained. 2 This
human phenotype underlines the essential impor tance of HIF sensing in controlling
multiple physiologic pathways, and future studies looking at whether human skin, in
par ticular, responds directly to decreases in atmospheric oxygen via HIF mediation
may provide a basis for the development of new strategies for the treatment of
anemia, hypoxia, and oxygen delivery in humans.
1. Ang SO, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genet. 2002;32:614-21.
2. Gordeuk VR, Sergueeva AI, Miasnikova GY, et al. Congenital disorder of oxygen-sensing: association of the
homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not
tumors. Blood. 2004;103:3924-32.
NELSON CHAO, MD
HEATHER GILBERT, MD, AND JOSEF T. PRCHAL, MD
Dr. Chao indicated no relevant conflicts of interest.
Drs. Gilbert and Prchal indicated no relevant conflicts of interest.
10
The Hematologist: ASH NEWS AND REPORTS
Artificial Blood – Not Too Sweet
Selecting Patients Most Likely to Respond to Therapy
Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based
blood substitutes and risk of myocardial infarction and death: a
meta-analysis. JAMA. 2008. [Epub ahead of print]
Mateo G, Montalbán MA, Vidriales MB, et al. Prognostic value of immunophenotyping multiple myeloma: a study by the GEM and the PETHEMA cooperative study
groups on patients uniformly treated with high-dose therapy. J Clin Oncol. 2008.
[Epub ahead of print]
oon after William Har vey described the circulation of blood
in the early 17th century, Christopher Wren unsuccessfully
experimented with replacing wine for blood. During a
cholera outbreak in the late 19th century, Gaillard Thomas also
failed in his attempts to substitute milk for blood. It was not until
1933 that the first successful blood substitution experiments
were performed. William Ruthrauff Amberson of the University of
Tennessee Medical School used hemolyzed red blood cells for an
exchange transfusion in a cat and demonstrated that he could
keep the animal alive for 36 hours. Unfor tunately, infusion of a
similar product into humans produced oliguria and bradycardia.
These toxicities were initially thought to be due to the lipids within erythrocyte membranes. Yet, when Dr. Amberson infused
hemoglobin free of red-cell membranes into a hemorrhaging
post-par tum woman who had depleted her hospital’s inventory of
cross-matched blood, she developed bradycardia and hyper tension, and ultimately died from renal failure. These pioneering
studies that spanned three centuries have demonstrated that
the ideal blood substitute is an elusive goal.
ultiple myeloma (MM) is a heterogeneous disease with a broad range
of biological and clinical features. 1,2 Multiple studies have therefore
attempted to identify genetic and biologic markers, as well as clinical
characteristics to define subgroups of patients. For example, prognostic factors such as beta 2 microglobulin and albumin form the basis of the
International Staging System, 3 which is predictive of disease course.
Conventional cytogenetics can identify patients with adverse outcome to conventional low- and high-dose therapies (i.e., 4;14 translocation or deletion of
chromosome 13). 4 More recent studies have used microarray profiling 5 and
array comparative genomic hybridization 6 to form the basis for defining mRNAbased and DNA-based prognostic subgroups of myeloma. Impor tantly, prognostic factors must be defined in a par ticular clinical context. For example, in
patients treated with novel therapies such as bor tezomib, chromosome 13
deletion and 4;14 translocation are no longer of adverse prognostic impor t. 7
Moreover, recent studies have utilized microarray profiling to define patient
populations with gene signatures predictive of response to specific therapies
(i.e., bor tezomib). 8
S
Today, the blood supply in the United States is safe and usually
sufficient to meet the needs of our patients. However, the current system does have two large fundamental problems. First,
our reliance on altruistic blood donation creates seasonal shor tages during the summer and winter holidays. Second, evolving
and emerging infections will always endanger the safety of transfused human products. In theory, a red blood cell substitute
would obviate both of these issues. A high-quality substitute
would also be helpful for use in patients who are difficult to
cross match, for individuals who will not accept transfusions of
human products, and for emergency infusions at the scenes of
trauma (civilian and military).
Most modern blood substitutes are either perfluorocarbons or
hemoglobin-based oxygen carriers. Perfluorocarbons are nonwater soluble, biologically iner t, ar tificial, organic fluids with a
high solubility for oxygen. Gas molecules are not chemically
bound to perfluorocarbons, but instead are absorbed and
released by simple diffusion. A large phase III trial using the perfluorocarbon, Oxygent, was halted early because of an increase
in stroke rates in patients who were undergoing cardiopulmonary
bypass. Hemoglobin-based oxygen carriers have held more promise. Four different methods have been used to avoid the toxicities induced by free hemoglobin: 1) cross-linking of the alpha
chains, 2) polymerization of the hemoglobin chain tetramers, 3)
conjugation of the hemoglobin to a larger molecule such as polyethylene glycol, and 4) encapsulating hemoglobin within liposomes. Since 1996, at least a dozen trials have been performed
that analyzed the utility of these agents in a variety of clinical
settings.
In a systematic review of the available literature on purified
hemoglobin-based blood substitutes published since 1980,
Natanson, et al. identified 70 trials, focusing only on the 16 randomized controlled trials involving 3,711 patients who received
one of five cell-free hemoglobin products. One product,
HemAssist, was cross-linked hemoglobin; three products,
Hemopure, Hemolink, and PolyHeme, were polymerized hemoglobin; and one product, Hemospan, contained hemoglobin conjugated to polyethylene glycol. Disappointingly, but not surprisingly,
the use of any of these products was associated with an almost
three-fold increased risk of myocardial infarctions. Overall mortality was only mildly worse (relative risk 1.30) in subjects
exposed to the blood substitutes. Fur ther analysis did not indicate that any one hemoglobin product or any one indication for
therapy was par ticularly worse than any of the others. These
results demonstrate that the use of the available cell-free hemoglobin products is associated with too much morbidity, and an
unacceptable rate of morbidity, to be of any clinical benefit.
M
Mateo and colleagues have recently carried out a prospective study of 685
newly diagnosed patients with myeloma treated uniformly with six alternating
cycles of vincristine, BCNU, melphalan, cytoxan, and prednisone (VBMCP)
alternating with vincristine, BCNU, adriamycin, and prednisone (VBAP) therapy, followed by melphalan 200mg/m 2 and autologous stem cell transplantation. The median progression-free sur vival (PFS) and overall sur vival (OS) were
37 and 67 months, respectively. In order to delineate patient subgroups with
differential outcome, CD138 positive bone marrow plasma cells were purified
and immunophenotyped prospectively as well. Impor tantly,
CD19+CD28+CD117-phenotype on CD138+BM plasma cells predicted poor
outcome, with significantly shor ter PFS and OS. An immunophenotype-based
staging system, defined on the basis of CD28 and CD117 expression on
tumor cells, identified poor-, intermediate-, and good-risk patient subgroups
with significantly different PFS and OS. In addition to its clinical utility, understanding the biologic significance of the obser ved antigen-expression profiles
conferring this differential outcome may both delineate mechanisms of sensitivity versus resistance to therapy and also yield insights into MM pathogenesis. Moreover, correlation of these phenotype profiles with microarray profiling
and aCGH analysis may identify, and yield, new insights into MM pathogenesis
to be exploited in novel, single agent or combination targeted therapeutics.
Several novel therapies are now available for myeloma, and the challenge is to
use them most effectively. These investigators are to be congratulated on
their major effor t of prospectively purifying patient tumor cells for phenotypic
analysis and correlation with clinical outcome. Although VBMCP/VBAP is no
longer utilized and incorporation of novel therapies such as bor tezomib into
the initial therapy pre-transplant improves response post high-dose melphalan
and autologous stem cell transplantation, 9 this study by Mateo and coworkers
is an example for future effor ts of how correlative science can inform the
selection of patients most likely to benefit from novel therapeutics.
1. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev
Cancer. 2002;2:175-87.
2. Hideshima T, Mitsiades C, Tonon G, et al. Understanding multiple myeloma pathogenesis in the bone
marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585-98.
3. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin
Oncol. 2005;23:3412-20.
4. Greipp PR. Prognosis in myeloma. Mayo Clin Proc. 1994;69:895-902.
5. Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic
event in multiple myeloma. Blood. 2005 Jul 1;106:296-303.
6. Carrasco DR, Tonon G, Huang Y, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9:313-25.
7. Jagannath S, Richardson PG, Sonneveld P, et al. Bor tezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21:151-7.
8. Mulligan G, Mitsiades C, Bryant B, et al. Gene expression profiling and correlation with outcome in
clinical trials of the proteasome inhibitor bor tezomib. Blood. 2007;109:3177-88.
9. Harousseau JL, Mathiot C, Attal M, et al. VELCADE/dexamethasone versus VAD as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: updated
results of the IFM 2005/01 trial. Blood (Annual Meeting Abstract). 2007;110:139a.
CHARLES ABRAMS, MD
KENNETH ANDERSON, MD
Dr. Abrams indicated no relevant conflicts of interest.
Dr. Anderson indicated no relevant conflicts of interest.
The Hematologist: ASH NEWS AND REPORTS
11
Erythrocyte Indigestion: A Surprising Role for the Mitochondrial
Pathway of Apoptosis in Reticulocyte Autophagy
Targeting NF-κB in CLL
Sandoval H, Thiagarajan P, Dasgupta SK, et al. Essential role for Nix in autophagic maturation of
erythroid cells. Nature. 2008. [Epub ahead of print]
Hewamana S, Alghazal S, Lin TT, et al. The NF-κB subunit
Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and
represents a promising therapeutic target. Blood.
2008;111:4681-9.
Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance
during reticulocyte maturation. Proc Natl Acad Sci USA. 2007;104:19500-5.
Kundu M, Lindsten T, Yang CY, et al. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood. 2008. [Epub ahead of print]
any dramatic changes of terminal mammalian erythroid
cell differentiation occur during reticulocyte maturation, including
completion of hemoglobin synthesis,
degradation of internal organelles,
conversion from aerobic to anaerobic
metabolism, and acquisition of a uniform biconcave discoid shape. Recent
publications have shed light on the
role of autophagy, an intracellular
process by which organelles are
degraded, in mitochondrial loss during
reticulocyte maturation. Two of the
studies have demonstrated that
knockout mice deficient in Nix, a BH3
domain-only member of the Bcl2 family of proteins, have retarded degradation and clearance of mitochondria in
reticulocytes. This inability to degrade
mitochondria leads to a shor tened
erythrocyte sur vival and anemia (i.e.,
par tially compensated hemolytic anemia). Because Bcl2 and its family of
proteins are key regulators of the
mitochondrial pathway of apoptosis,
the role of Nix in reticulocyte mitochondrial degradation suggests that it
can mediate either apoptosis or survival, depending upon circumstances
of the individual cell.
M
Figure
Model of Nix-mediated autophagic clearance of
mitochondria from reticulocytes. Nix interacts
with mitochondria in reticulocytes that have completed heme synthesis. Nix induces depolarization
of the inner mitochondrial membrane, and the
depolarized mitochondrion is sequestrated in a
double membrane structure termed the
autophagosome. The autophagosome subsequently
fuses with a lysosome forming the autolysosome.
Proteolytic enzymes from the lysosome degrade
the inner membrane of the autolysosome and partially degrade the sequestered depolarized mitochondrion. The non-degraded contents of the
autolysosome are extruded from the
reticulocyte.
In nutrient-deprived cells, autophagy
may be an alternative to apoptosis in
that essential metabolites required for
sur vival of the nutrient deprivation are
salvaged by degrading organelles such as the mitochondria and recycling the crucial metabolic products. 1 Similar to nutrient deprivation, maturating reticulocytes reach a crucial stage
when death can result if the autophagic process is disrupted. Mitochondria appear to be
both degraded and extruded from the maturing reticulocyte by autophagy. 2 (See figure.) The
failure of mitochondria to undergo autophagy in reticulocytes appears to be detrimental
because a similar hemolytic anemia with mitochondria-retaining erythrocytes as found in Nix
knockout mice was found in knockout mice with deficiency of Ulk1, the mammalian homologue
of atg 1p, a mitochondrial autophagy regulatory protein in yeast.
In the sequence of events in mitochondrial autophagy in reticulocytes, Nix acts at the stage
of mitochondrial depolarization and targeting for inclusion in autophagosomes. Nix interacts
with the outer mitochondrial membrane, leading to loss of inner membrane polarization. 3
Reticulocytes from Nix-deficient mice retain polarized mitochondria, but they are localized to
areas adjacent to autophagosomes in reticulocytes. This result suggests that targeting of
the mitochondria to the autophagosomes may be intact, but Nix’s induction of mitochondrial
depolarization is required for normal mitochondrial incorporation into autophagosomes.
Fur ther evidence for this role of Nix in mitochondrial depolarization is that chemical depolarization of mitochondria in reticulocytes from Nix-deficient mice leads to their autophagic
clearance. Unlike reticulocytes and erythrocytes from Nix-deficient mice, those from Ulk1deficient mice have retention of ribosomes and mitochondria. Fur thermore, the retained
mitochondria in the Ulk1-deficient mice are not localized to areas adjacent to autophagosomes, suggesting that Ulk1-deficient mice have a defect at a different point than do Nixdeficient mice in the reticulocyte autophagy pathway.
he NF-κB family of transcription factors has been
implicated in diverse cellular processes, including
cell proliferation, differentiation, sur vival, and
inflammatory responses, among numerous others. At
least three NF-κB cascades have been characterized:
the classical or canonical pathway, which is induced by
cy tokines such as TNFα; the non- cl assi cal , or al ternati ve
pathway, whi ch i s tri ggered by BA FF and C D40 l i gati on;
and the aty pi cal pathway, whi ch i s engaged by DNA damage. A cti v ati on of NF- κB leads to transcription of
numerous genes, many of which (for example, XIAP
and Bcl-xL) ser ve sur vival functions. Not unexpectedly,
NF-κB activation occurs in many tumor types, par ticularly hematologic malignancies. For example, multiple
myeloma cells have long been thought to depend heavily upon NF-κB activation for their sur vival, and several
recent studies have documented a high incidence of
abnormalities involving genes associated with NF-κB
activation in patient-derived myeloma cells. In addition,
NF-κB activation is characteristic of AML cells in general, as well as in AML stem cells. A corollary of
these obser vations is that NF-κB represents a logical
candidate for therapeutic inter vention.
T
CLL is an accumulative disease of mature, differentiated lymphocy tes. Although activation of the classical
and alternative pathways has been implicated in CLL
cell sur vival, the clinical relevance of these obser vations has not been clearly defined. However, a recent
study by Hewamana, et al. may shed significant light
on this issue. In this study, the authors examined NFκB DNA binding, reflected by EMSA assays, in cells
from a series of patients with CLL and sought correlations with more established prognostic indicators.
They also tested whether the extent of NF-κB activation predicted resistance of cells to conventional and
novel agents. While the authors obser ved considerable
inter-sample variability in basal NF-κB activation status, clear correlations were obser ved between activation and cer tain known negative prognostic indicators
(e.g., high white count, shor t doubling time), although
not between others (e.g., ZAP-70 expression).
Interestingly, cells exhibiting high basal NF-κB activity
were less sensitive to the established agent fludarabine, but more sensitive to the novel agent, LC-1, a
par thenolide analog that inhibits IKK and has recently
been shown to be active against AML stem cells.
Fur ther studies of maturing reticulocytes have the potential to determine the specific range,
targeting, and fate of the organelles that are removed by autophagy. This information will not
only interest those studying erythropoiesis, but also interest those researchers and physicians interested in other cellular processes that involve autophagy, such as differentiation,
aging, and sur vival following chemical or physical stress.
One implication of this study is that, as recently suggested in the case of other hematologic malignancies
such as multiple myeloma and AML, the NF-κB pathway may not only be an impor tant prognostic determinant in CLL, but could also represent a logical target
for pharmacologic inter vention in this disorder. In this
context, the results of a recent preclinical study suggested that synergistic interactions between the proteasome inhibitor bor tezomib and histone deacetylase
inhibitors in primary CLL cells involved, at least in
par t, NF-κB inactivation. 1 The broader implication of
the present study is that, as more sophisticated gene
and protein profiling classification systems are developed in CLL and other hematologic malignancies, their
ultimate benefit may lie in guiding the development of
more rational, mechanism-based, targeted forms of
therapy.
1. Lockshin RA, Zakeri Z. Int J Biochem Cell Biol. 2004;36:2405-19.
2. Koury MJ, Koury ST, Kopsombut P, et al. Blood. 2005;105:2168-74.
3. Diwan A, Koesters AG, Odley AM, et al. Proc Natl Acad Sci USA. 2007;104:6794-9.
1. Dai Y, Chen S, Kramer LB, et al. Interactions between bor tezomib
and romidepsin and belinostat in chronic lymphocytic leukemia cells.
Clin Cancer Res. 2008;14:549-58.
MARK KOURY, MD, AND CHARLES PARKER, MD
STEVEN GRANT, MD
Drs. Koury and Parker indicated no relevant conflicts of interest.
Dr. Grant indicated no relevant conflicts of interest.
12
The Hematologist: ASH NEWS AND REPORTS
T H E
H E M A T O L O G I S T - I N - T R A I N I N G
2008 MMSAP PARTICIPANTS
he Minority Medical Student Award Program (MMSAP) encourages
minority medical students to purse an interest in hematology research. For
an eight- to 12-week period, MMSAP participants will work closely with
their mentors on a hematology-related research project. The subjects investigated
by this year ’s students include lymphoma, leukemia, sickle cell anemia, thalassemia, and stem cells. The awardees will also have the opportunity to present
the results of their research at ASH’s annual meeting in December.
T
This year ’s program has the largest number of participants yet, including three
returning students. Each award recipient will receive the support of a research
mentor and a career-development mentor, travel stipends to attend medical meetings, and a subscription to The Hematologist and Blood.
Akram Shayeb
Andres Bur
April Szafran
University of Puer to Rico
University of Pennsylvania
University of Illinois at Chicago
School of Medicine
School of Medicine
College of Medicine
San Juan, PR
Philadelphia, PA
Chicago, IL
Awet Abraha
Candace Johnson
Christina Lawson
Wayne State University
Wayne State University
Howard University
School of Medicine
School of Medicine
College of Medicine
Detroit, MI
Detroit, MI
Washington, DC
Daniel Hayward
Edward E. Robertson
Jaime Brewer
Thomas Jefferson University
Keck School of Medicine of the
University of Illinois at Chicago
Jefferson Medical College
University of Southern California
College of Medicine
Philadelphia, PA
Los Angeles, CA
Chicago, IL
Nadine Thompson
Nicole Jones
Nnenaya Agochukwu
Virginia Commonwealth University
Wayne State University
Louisiana State University
School of Medicine
School of Medicine
School of Medicine
Richmond, VA
Detroit, MI
Shrevepor t, LA
WHAT’S NEXT > >
Olabunmi Agboola
University of Illinois at Chicago
College of Medicine
Chicago, IL
N E W S
A N D
>
Look for an article about returning MMSAP participant Olabunmi Agboola and her mentor Christopher Flowers, MD,
of Emory University, in the September/October issue.
R E P O R T S
ASH Hosts Thrombosis Surveillance Workshop
ROY SILVERSTEIN, MD, AND GARY EDWARD RASKOB, PhD
Dr. Silverstein is Professor of Molecular Medicine and Chairman of the Department of Cell Biology at the Lerner Research Institute. He is also Chair of the ASH
Committee on Government Affairs.
Dr. Raskob is Dean of the College of Public Health, Professor of Epidemiology, and Professor of Medicine at The University of Oklahoma Health Sciences Center.
enous thrombosis affects up to 1 million Americans each year and has
been called by some the “silent killer.” Despite the large impact thrombosis has on the population, the United States has not yet developed/implemented a sur veillance system for thrombosis. To improve understanding of the
scope and scale of the problem and begin to identify key elements in a sur veillance system, ASH convened a successful workshop in Washington, DC, on June
12.
V
ASH worked closely with the Centers for Disease Control and Prevention (CDC)
and National Heart, Lung, and Blood Institute (NHLBI) in planning the workshop with the ultimate goal of identifying key questions that need to be answered
through a national sur veillance system and scientific approaches that can answer
them. ASH scheduled the workshop in the first half of the year because interest
about thrombosis within the U.S. Department of Health and Human Ser vices is
growing. The Surgeon General’s Office is expected to issue a “Call to Action”
this year stating that the United States is facing a major public health crisis
regarding venous thrombosis, and leadership at the CDC National Center on
Birth Defects and Developmental Disabilities (NCBDDD) identified thrombosis
as one of its top four priorities in 2008.
The Hematologist: ASH NEWS AND REPORTS
We had the privilege of jointly chairing the one-day symposium that assembled a
group of 30 participants including representatives from relevant federal agencies,
patient groups, and the medical and public health communities. Experts from various subspecialties discussed their “front-line” perspective of dealing with venous
thromboembolic disorders (VTE). The subspecialty experts included representatives from the following communities: pediatric and adult hematology, obstetrics
and gynecology, geriatrics, emergency medicine and trauma, radiology, and surger y. A hospitalist and intensivist were also present. In addition, experts in epidemiology and health-care policy leaders lent their expertise to the discussion.
A workshop writing committee is developing a summar y of the meeting’s deliberations and will produce a report identifying recommendations and next steps. Once
finalized, the document will be shared with the ASH membership, relevant federal agencies, patient groups, and the medical and public health communities.
D r. R a s k o b c o n s u l t s f o r a n d r e c e i v e s h o n o r a r i a f r o m B a y e r, B M S ,
D a i i c h i - S a n k y o , G S K , J o h n s o n & J o h n s o n / S c i o s , P f i z e r, S a n o f i aventis, and ThromboGenics.
13
T H E
H E M A T O L O G I S T
A D V O C A T E
PATIENTS AND POLITICS:
INTERPRETING THE FOOTPRINTS OF DONKEYS AND ELEPHANTS FOR PATIENTS
MARGARET RAGNI, MD, MPH
Dr. Ragni is Professor of Medicine in the Division of Hematology/Oncology at the University of
Pittsburgh and Director of the Hemophilia Center of Western Pennsylvania.
Editor’s Note: This is the second in a series of articles illustrating how hematologists can become involved with the presidential election. ASH members are encouraged to
take advantage of and create new opportunities to become involved in the election and particularly to share their views about health-related issues with the candidates.
o election politics leave you cold? Have political pundits got you down? Have you
grown tired of the political bickering? One possible solution has been offered by
Vice President for Public Policy Glenn Mones at the National Hemophilia
Foundation (NHF). Mr. Mones is developing something refreshing and relevant. He is creating a patient-focused guide about the upcoming presidential election and its potential
impact on health care in general and on individuals with bleeding or clotting disorders in
particular. Dr. Craig Kessler, of Georgetown University, and chair of NHF ’s Medical and
Scientific Advisor y Committee (MASAC), asked Mr. Mones to give a short presentation
on the subject at their recent meeting in Chicago. Dr. Kessler mentioned that he had
received a lot of positive feedback on the presentation; thus, the idea of the patient guide
came about. Mr. Mones’ analysis is not intended to be an endorsement of any candidate,
but rather a look at where the candidates stand on key health-care issues and how their proposals might affect individuals with bleeding and clotting disorders.
D
As Mr. Mones describes, “This is a campaign: We are hearing what the candidates are
saying but not necessarily whether they will carr y through on their promises, nor whether
their policies will work. None of the plans are detailed enough to determine how well they
would meet the particular needs of the bleeding and clotting disorders community.”
While Mr. Mones’ guide does not attempt to solve your patients’ health-care issues, his
effort highlights how one can make this presidential campaign more relevant to the hematology community. Interested readers can obtain the guide by contacting the National
Hemophilia Foundation at 800-42-HANDI, or by visiting www.hemophilia.org. The chart
to the right displays a few examples from the guide. ASH has also prepared a side-by-side
comparison of the presidential candidates’ positions on health care that is available on the
ASH Web site at www.hematology.org/policy/news/02142008.cfm.
D r. R a g n i i s a m e m b e r o f t h e m e d i c a l / s c i e n t i f i c a d v i s o r y c o m m i t t e e a t
the National Hemophilia Foundation.
DEMOCRATS
REPUBLICANS
Tax credits
for individuals
Would make tax credits
and subsidies available
to help with premiums
for families who need it
Would remove tax credits for individuals buying
insurance
Would not create a
national health plan
National
health plan
Would create a national
health plan as an option
for all Americans, providing quality care at an
affordable rate, with neither premiums nor benefits affected by health
status
Cost
containment
strategies
Would seek to contain
costs through a variety
of means, including better use of technology,
more prevention education, and allowing
Congress to reduce
drug costs
Would promote the use
of alternative providers
and venues, such as
nurse practitioners and
walk-in clinics
Would suppor t cost containment and allow
Congress to work on
reducing drug costs
Would seek to lower
drug costs and make
drug companies reveal
more pricing data
Would suppor t cost containment through more
prevention education
Would suppor t investment in prevention and
care of chronic illness
Drug costs
Prevention
and care of
chronic illness
O B I T U A R Y
Oscar D. Ratnoff, MD
(1916- 2008)
D r. O s c a r D . R a t n o f f w a s t h e c o n s u m m a t e
triple threat. He was an excellent clinician,
b a s i c a n d c l i n i c a l r e s e a r c h e r, a n d t e a c h e r
a n d m e n t o r. H i s 3 0 2 p u b l i c a t i o n s a r e f i l l e d
with seminal observations that moved his
field forward in the 1950s to the 1980s.
His observations populated 29 Journal of
Clinical Investigation and 63 Journal of
Laboratory Clinical Medicine publications, many with trainees as
first authors.
D r. R a t n o f f s t a r t e d h i s i n v e s t i g a t i v e c a r e e r i n l i v e r d i s e a s e ,
which introduced him to plasma proteins. At Johns Hopkins with
D r. C a l v i n M e n z i e s , D r. R a t n o f f d e s c r i b e d a s i m p l e m e t h o d t o
measure fibrinogen. In 1950, he moved to Cleveland and Case
We s t e r n R e s e r v e U n i v e r s i t y ( C W R U ) . I n 1 9 5 5 , D r. R a t n o f f a n d
D r. J a n e C o l o p y r e p o r t e d o n a p a t i e n t , J o h n H a g e m a n , w h o h a d
reduced surface-activated blood coagulation times without
b l e e d i n g . H e a n d D r. E a r l D a v i e l a t e r i d e n t i f i e d , i n 1 9 6 1 , t h e
missing protein in the Hageman trait as factor XII and showed
that it activated factor XI. This collaboration led directly to publication of the coagulation cascade hypothesis in 1964. They
observed that isolated factor XII autoactivates on negatively
charged surfaces leading to factor XI activation and then a
waterfall of proteolytic reactions. At the time, the model synthesized the biochemical basis of blood coagulation and led to
44 years of refinements.
D r. R a t n o f f h a d a l o n g - s t a n d i n g c o l l a b o r a t i o n w i t h D r. I r w i n
L e p o w, t h e d i s c o v e r e r o f p r o p e r d i n i n t h e c o m p l e m e n t s y s t e m ,
and together they described the C1 inhibitor of the first components of the complement system. In 1969, Drs. Ratnoff and
14
George Naff showed that the C1 inhibitor inhibits plasma
k a l l i k r e i n a n d p l a s m i n , a n d , w i t h D r. C h a r l e s D . F o r b e s ,
described in 1970 that the C1 inhibitor also inhibits factor XIIa
and factor XIa. In the 1970s, as part of an evaluation of a
patient who had a long APTT without bleeding, but had normal
f a c t o r X I I , D r s . R a t n o f f a n d H i d e h i k o S a i t o s i m u l t a n e o u s l y, w i t h
t h e l a b o r a t o r i e s o f We u p p e r, C o l m a n , a n d K a p l a n , d e s c r i b e d
high-molecular-weight kininogen deficiency in humans.
D r. R a t n o f f ’s c o n t r i b u t i o n s t o m e d i c i n e w e r e r e c o g n i z e d b y h i s
election to the American Society for Clinical Investigation, the
Association of American Physicians, and the National Academy
of Sciences. He served as President of ASH and was selected
to present the Henry M. Stratton Lecture in 1972. At CWRU
and University Hospitals, he served as Division Chief of
Hematology and Oncology and interim Chairman of the
D e p a r t m e n t o f M e d i c i n e . To h i s t r a i n e e s , h e w a s t h e s k i l l f u l a n d
t a l e n t e d e d i t o r, t i r e l e s s r e v i e w e r, a n d c o n s t a n t s c i e n t i f i c p r o tagonist, but his greatest legacy is his influence on countless
physicians, internists, and hematologists as the accomplished
physician-scientist.
D r. R a t n o f f i s s u r v i v e d b y h i s w i f e , M a r i a n F o r e m a n R a t n o f f , h i s
d a u g h t e r, M a r t h a R a t n o f f , a n d s o n , W i l l i a m D a v i s R a t n o f f , M D .
For those who wish to donate, contributions may be made to
t h e D r. O s c a r D . R a t n o f f R e s e a r c h a n d E d u c a t i o n F u n d a t t h e
C a s e We s t e r n R e s e r v e U n i v e r s i t y S c h o o l o f M e d i c i n e .
– A l v i n H . S c h m a i e r, M D , a n d S t a n t o n L . G e r s o n , M D
D r. R a t n o f f w a s p r o f i l e d i n t h e J a n u a r y / F e b r u a r y 2 0 0 8 i s s u e o f
T h e H e m a t o l o g i s t a s p a r t o f A S H ’s o n g o i n g s e r i e s f o r t h e 5 0 t h
a n n i v e r s a r y. T h e a r t i c l e c a n b e a c c e s s e d o n l i n e a t w w w. h e m a t o l o g y. o r g / p u b l i c a t i o n s / h e m a t o l o g i s t / J F 0 8 / p r o f i l e s . c f m .
The Hematologist: ASH NEWS AND REPORTS
ASH’s 50th Anniversary: Profiles in Hematology
William Dameshek: Compassionate Clinician and Gifted Teacher
ROBERT S. SCHWARTZ, MD
Dr. Schwartz is a Deputy Editor of the New England Journal of Medicine.
illiam Dameshek (1900-1969) was the preeminent American clinical hematologist of
his time. A polymath, his interests ranged
from diseases of the blood to pre-Columbian statuettes. He was a lead investigator in the first-known
multi-institutional trial of chemotherapy (nitrogen
mustard for Hodgkin lymphoma). Dr. Dameshek pioneered in the treatment of immune thrombocytopenia
with corticosteroids, introduced antimetabolite therapy
for autoimmune diseases, developed the concepts of
the myeloproliferative and lymphoproliferative disorders, and proposed that CLL is the result of a gradual accumulation of lymphocytes. He was the founder
of Blood, an architect of the American Society of
Hematology, and an organizer of the International Society of Hematology (ISH).
W
“
Dr. Dameshek was named
Ze’ev at his birth in Voronezh,
Russia, and, at the age of
three, was brought to the
United States by his parents,
who settled in Medford, MA,
and renamed him William. An
exceptional student at Boston’s English High School (the oldest public high
school in America), he went to Har vard College, and in 1923 he graduated from
Har vard Medical School and married Rose (Ruddy) Thurman.
Above all, he was deeply
empathetic with patients
for whom there were few
effective treatments.
”
arrive in his office on Monday morning with a bundle of lined white paper on
which he had, over the weekend, written in characteristic green ink his latest
thoughts on PNH, CLL, or myelodysplasia. On some Mondays, he would arrive
bursting with a wonderful new idea about the origin of lymphomas, or the relation
between PNH and aplastic anemia, or why immune thrombocytopenia develops in
systemic lupus er ythematosus. Soon after we (puppies) had yelped our objections
to the latest idea, it would appear as an editorial in Blood.
Dr. Dameshek demanded from us fellows his own level of enthusiasm, commitment, and effort. It wasn’t easy to emulate the boss. On Friday, October 4, 1957,
the day the Sputnik satellite went into orbit, we received a memorable lecture on
our deficiencies. Later, he apologized even though we knew that he meant ever y
word.
Patients came from ever ywhere to seek Dr. Dameshek’s counsel. Luminaries
arrived regularly. He collected art, lived in a beautiful house in Brookline, loved
music (Serge Koussevitzky was his patient), and entertained grandly thanks to
Ruddy. Dressed by Louis, Boston’s high-end haberdasher, Dr. Dameshek cut a
stylish figure. He was, from outward appearances, the antithesis of the staid,
underpaid Boston academic. He would brush off petty jealousies with a shrug.
His favorite response to the critics was, “Ever y knock is a boost.”
Dr. Dameshek had an extraordinar y influence on the development of hematology
in America. He used his intelligence, independence, and influence in ways that
benefited not only hematologists but also patients. His legacy is unique.
During his internship at Boston City Hospital, he
worked with Dr. R alph Larrabee, a Tufts professor
who had established a “Blood Laborator y ” in the
basement of the hospital. Dr. Dameshek’s first
research paper was titled “The reticulated blood cells
— their clinical significance.” Dr. Dameshek was also
drawn to hematology by George Minot, director of
the Thorndike Memorial Laborator y of the hospital,
who in 1925 was treating pernicious anemia — then
a fatal disease — with raw liver. In 1939, Dr.
Dameshek established the Blood Research
Laborator y at what was to become the New England
Medical Center (now Tufts Medical Center). There
he did the work that brought him international recognition.
Dr. Dameshek was a gifted teacher. He ran the most popular course (hematology)
for medical students at Tufts University School of Medicine; his Saturday morning hematology Grand Rounds at the New England Medical Center were legendar y. He trained more than 100 hematologists from 20 countries. Former
trainees still remember walking rounds with Dr. Dameshek — 20 fellows and students trailing the master through the hospital. Dr. Dameshek knew better than
any of us how to take a histor y, perform a physical examination, and interpret a
blood smear. In the hallway, after leaving the patient, he would quiz, cajole, and
tease the fellows but never embarrass, and never parade his knowledge. He could
effortlessly admit, “I don’t know.” (“ We’ll vote,” he’d say about a difficult problem or decision.) Above all, he was deeply empathetic with patients for whom
there were few effective treatments. He never denied them hope, never seemed
rushed, never failed to touch them.
Dr. Dameshek was not a laborator y investigator. He was a busy clinician who
took the time to think deeply about his patients and their diseases. He was tireless. He wrote five books and more than 350 articles and editorials. He would
The Hematologist: ASH NEWS AND REPORTS
From left to right: 1) Dr. Dameshek points to a world map. 2) From left to right: Drs.
Ray Owen, Theodore Spaet, Ernest Beutler, William Dameshek, and Leon Jacobson
converse during a symposium sponsored by Dr. Beutler at City of Hope in 1961. 3)
Dr. Dameshek pictured at his 60th birthday celebration.
Photos courtesy of Drs. Robert Schwartz and Ernest Beutler.
15
W H A T ’ S
O N
T H E
W E B
MARK YOUR CALENDAR
The ASH Web site offers a convenient way for ASH members to
find information relating to upcoming Society events and provides
easy access to the many valuable products and ser vices offered by
ASH.
JULY
Participate in A SH’S 50TH ANNIVERSARY and learn more
about the rich histor y of ASH and hematology by visiting
www.hematology.org/about/50thanniversary. On this Web page you
can meet legends in hematology and read their oral histories, in
which they reflect upon their careers. Check out the latest additions
for Drs. Ernest Beutler and Joseph F. Ross in the Legends of
Hematology section at www.hematology.org/education/legends.
The World Congress on Controversies in Cardiovascular Diseases
3–6
Berlin, Germany
www.comtecmed.com/ccare
9 – 12
The 37th Annual Scientific Meeting of the Society for Hematology and Stem Cells
Boston, MA
www.iseh.org
21 – 26
Fourth International Barth Syndrome Conference
Clearwater, FL
www.barthsyndrome.org
22
Annual meeting early-bird registration opens for ASH members
Washington, DC
www.hematology.org
AUGUST
Add your name to the “FIND A HEMATOLOGIST” resource.
This is an online ser vice to connect patients with hematologists in
their area. Help us make this resource even more valuable by agreeing to be listed in our public director y. Go to www.findahematologist.org for more information.
Go to www.hematology.org/education/awards/ifa.cfm to download
your letter of intent for the EHA-A SH INTERNATIONAL
FELLOWSHIP AWARD. Letters are due by September 4. The
EHA-ASH International Fellowship Award is offered in partnership with the European Hematology Association (EHA) to provide
hematologists in training or early in their careers the opportunity to
conduct research in another countr y.
5
Annual meeting advance registration opens to members and non-members
Washington, DC
21
Annual meeting abstract submission deadline
Washington, DC
www.hematology.org
21 – 29
Hematology and Medical Oncology Board Review
Washington, DC
Get up-to-date ANNUAL MEETING information at www.hematology.org/meetings/2008/index.cfm. Join ASH in San Francisco for
its 50th anniversar y celebration.
www.hematology.org
www.hemoncboardreview.com
27 – 28
Workshop on Vasculopathy in Sickle Cell Disease
Bethesda, MD
Read THE HEMATOLOGIST ONLINE (www.hematology/publications/hematologist) and catch up on the latest news in the field of
hematology right on your desktop.
www.sicklecellmeeting.net
SEPTEMBER
4
EHA-ASH International Fellowship Award letter-of-intent deadline
Washington, DC
www.hematology.org
5
Institutional Insights in Multiple Myeloma
Atlanta, GA
www.multiplemyeloma.org
5–7
10th International Conference on Chronic Myeloid Leukemia
Boston, MA
www.esh.org/agenda08.htm
12 – 14
Annual Meeting of the Society for the Advancement of Blood Management
Baltimore, MD
www.sabm.org
16 – 17
NIDDK: Heme Regulation During Erythropoiesis
Bethesda, MD
www3.niddk.nih.gov/fund/other/hemeregulation/index.htm