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EDITORIAL
Hematopoietic
Stem
Possible
Lymphoblastic
Myeloid
Cell
Theory
Conversion
Leukemia
By Dane
C
URRENT
EVIDENCE
in Relation
of Chronic
R. Boggs
SUGGESTS
that
chronic
myeloid
leukemia
(CML)
must
be considered
a clonal
disease
of a pluripotent
poietic
stem cell compartment.
The Philadelphia
chromosome
(Ph’
ity (translocation
of a portion
of the
lOng
arms
of chromosome
chromosome
patients
the
eosinophils,
plus the
with
twins4
is found
91)
of red cells,
observations
CML
indicate
disease
cism
or in bone
for
probably
neutrophils,
monocytes,
The
so that eventually
stem
cells
may
chemotherapy
is given,
cell
varies
various
from
myeloid
occasional
Blastic
crisis,
characterized
tion
of
patient
the
most
common
failure
immature
cells,
underproduction
of
chromosome
studies,
clone
of abnormal
blast
crisis
From
most
mature
blast
stem
have
been
the Department
nature
who
had
isozymes.6
heterozygous
red
of
mosaiAs
for
cells,
a growth
CML
isozymes,
isozymes.
stem
cell,
megakaryocytes,
advantage
recover
at least
cause
of red
of
over
normal
commonly
myeloblasts
platelets,
cells
in addition
observed
to
to the
acquire
university
in
levels
patients
with
continued
and
of
the
red
Ph
‘
clone.
School
of
‘
Based
of yet
Patients
Ph
is
but
cells.
to acquisititn
a second
CML,
overproduc-
promyelocytes,
and
of Pittsburgh
appearing
stem
cell defect
various
cellular
in blood
with
to be due
normal
The
into
cells.
death
maturation
appears
a
as reflected
and
of
with
at least.7
of feedout
neutrophils,
crisis
of Medicine.
has
months
degree
of platelets,
by increasing
identical
clonal
to sex chromosomes
or
disease
begins
in a single
patients
to patient,
leukocytes,
These
from
all active
stem cells bear the Ph’.
detected
in vitro3
and
further,
if intensive
marrow
and lose the Ph ‘ defect
for some
is not identical
in all patients
in that the
paths
The
certain
or
in precursors
nonleukemic
patients
eosinophils,
affected
virtually
still be
their
for
mosaic
hemato) abnormal22 onto
as monocytes.3
or lymphocytes
systems.
of affected
in respect
is that the
but
well
cells
from
heterozygous
remained
were
uniform
explanation
basophils.
stem cells
Normal
cells
cellular
by studies
cells
precursors,
platelets2
as
the Ph” in skin
marrow
or were
nonmyeloid
pluripotent
in neutrohil
selected
suggested
but myeloid
cells
Thus,
the simplest
and
of
chromosomes5
developed,
only
probably
to find
involvement
is further
ofsex
not
and
failure
to
or
going
other
Medicine.
on
another
into
abnormal
Pittsburgh.
Pa.
15261.
Submitted
February
Supported
in part
27, 1974.
by
Grant
(A M!3452)
from
the National
Institute of Arthritis
and
Metabolic
Diseases.
A ddress
burgh
for
School
1974
Blood, Vol.
reprint
requests:
of Medicine,
by Grune
44,
No.
Dr.
Dane
Pittsburgh,
Pa.
& Staiton,
3 (September),
R.
Boggs,
Department
of
Medicine.
university
of
Pitts-
15261.
Inc.
1974
4.49
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450
DANE
chromosome,4
lose
therapy,
and
In acute
red
cell
myeloid
In this
The
be
types
marked
AML
omitted
is
difficult,
there
are
different
might
minor
in
erythroblasts
within
potent
stem
ofblastic
the
aforementioned
cell
system.
istics
mixed
of lymphoblasts
with
smears
sense
to
steroid
steroid
response
probability
Wright’s-stained
other
patients
that
therapy,
or
of
given
prednisone,
from
60
80
x
by
little
which
allows
with CML
effect
in AML,
Ifthey
were
in a patient
with
blastic
conversion
about
A
the
structure
variety
changes
a relatively
In vitro
of
in murine
direct
culture
is ofsome
lymphoblastic
CML,
but
ofCML
of the
techniques
stem
does
system.
Thus,
be expressed
the
occasionally
above
that
seem
may
in whom
a disease
still
pro-
makes
some
of the
pluri-
another
to make
preexisting
Ph
had
the
Such
form
sense
at first
with
on
CML
positive
smears
were
coded,
ALL.
and
repeatedly
It may
identification
but
ALL
be
can
study.9
during
prednisone,
a complex
of
be
of
vincristine,
protocol
for cell type.
The response
to prednisone
and vincristine,”
with
these
in
rethat
predicted
of
blasts
died
usually
significance
One
which
she
who
character-
morphologic
leukemia
0,
‘
morphologic
However,
not.
1 wk
virtually
no implications
in blast crisis
mor-
Promyelocytes
the
smears.
These
with
AML
or
for
to
these
representing
patient
suggestion
in acute
second
developed
complete
remission
phosphamide,
and
the third
remitted
therapy
ofpatients
of
morphologic
mg/day,
lOt/liter
not.
being
blasts
AML
such
cell
fairly
in AML.
of
as
and
lymphoblasts.
response
0.9
observed
always
one
of CML
observers.
were
while
lack
exceeding
declined
they
is
not
megaand
in CML.
the
by experienced
proof
sponds
in
stem
not
cell.’#{176} All
does
immature
of
monocyte,
with
in which
be
of the
it
the
patients
phase
very
would
seen
that
basophilic
expression
indeed
conversion
three
from
lymphoblastic
is in no
raise
one
predominant
Megakaryo-
thought
I have
type”
to
occur,
from
slides
to a blastic
called
“Schilling
lymphoblastic
seen
converted
and
I want
be
of CML
the
techniques,
may
disease
crisis
concept
may
of
clinical
can
predominate
the
namely,
I have
in the
of a clonal
a
and
current
re-
similar.
proerythroblast.
abnormality
they
with
promyelocyte,
recognition
involve
reappear
rather
variable,
but
differences
became
conversion
glance,
but
myelomonocytes.
become
sense
is quite
are
or
list,
myeloblastosis,
may
cell
ofCML
impossible,
blastic
following
also
and
eosinophilic
syndromes,9
that
as
predominate
this
expressions
morphologically
remission
crisis
morphologic
anticipate
predominate,
blastic
not
phase
abnormalities
with
“myelomonocyte,”
if
a CML-like
chromosomal
of AML
from
only
to
recurs.8
promyelocyte,
diverse
slightly
and
expression
are
phologically
was
disappear
megakaryocyte
Since
one
(AML)
may
monocyte,
karyocytes
a return
crisis
leukemia
a myeloblast,
promyelocyte,
cytic
with
and
respect
morphologic
may
second
it as blastic
precursors
lapse.4
cell
the
reacquire
R. BOGGS
a
patients
the
blood
infection.
The
and cycloof multidrug
of
a number
agents
with
interest.
we
might
alternatively,
might
occur
hematopoietic
are
now
consider
it chance
there
is reason
from
consideration
stem
available
development
to believe
that
of current
of
ALL
lymphoevidence
cell system.
which
allow
measurement
cells.
Response
of plethoric
mice
to erythropoietin
measure
of stem
cells feeding
the erythroid
compartment.’2
of cells
in semisolid
media
measures
a cell pluripotent
of
is
for
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EDITORIAL
451
iieutrophils,
monocytes,
and eosinophils,3
and liquid
culture’3
and culture
of
cells in diffusion
chambers
implanted
in animals’4
probably
measure
growth
and the progeny
of the same
cell (these
in vitro
techniques
are the only
stem
cell assays
which
have
also been
applied
to man).
Transplantation
marrow
cells,
spleen
cells,
nucleated
blood
cells,
peritoneal
cells,
cells
into
lethally
colonies,
monocytes,
irradiated
medium-sized
round
cytogenetic
sue can
populating
be
repopulated
lymphoid
by
tissue.’7
sayed
by
the
spleen
(as
appears
that
is a murine
the
However,
stem
entirely
regards
settled.
changes
of
the
producing
long
techniques
in which
mixed
extreme
in
marrow
cell
colonies
There
and
more
of
primitive
has
stem
these
stem
pluri-
mice
From
is pluripotent
experi-
determined
also be
irradiated
is shielded.’8
tis-
cell
not been
cells can
sublethally
is
myeloid
with
cells
recell is capable
circumstances
which
These
populations.
spleen
of a still
stem
cell
these
for
is in DNA
murine
size.
this
all
spleen
colonies
as-
or
in
studies
blood
it
cells,
The
are in agreement
hypothesis
that
there
differentiation
observations
that
primarily
structure
the
(Fig.
in G0
or
INACTIVE
CELLS
1).
in a very
by other
concatenation
of
and an alternate,
unitarian
theory
in which
differentiates
into a given
cell type
according
to the stage
of the cell cycle2’
has not been
STEM
as
compartment
measured
of
inis not
of compartments
exact
multiple
theories’9)
of increasing
is either
proportion
synthesis.2#{176}
partments
is far from
clear,
is only one stem cell which
probability
function
related
of
versus
polyphyletic
stem cell assays
rarely
This has led to the
consists
greater
a single
and
compartments
for
a much
concerning
neounitarian,
The various
in compartment
evidence
, while
debate
(unitarian,
transplanted
,
the
stem
colonies.’5
contain
neutrophils,
as well as unidentified
share
common
ancestry
the spleen
colony-forming
technique
long-standing
cells
concatenated
Part
or
that
mouse
exudate
lymphocyte.
dividual
are
cells which
Whether
colony
mice
the
of spleen
cells and lymphoid
tissue
opposed
to transplanted)
irradiated
including
“pure”
is activation
heavily
there
formation
in rats
under
there
to
certain
circumstances,’6
and megakaryocytes
either
and
differentiation
for colony-forming
1). Endogenous
leads
under
cells,
in
in mice
or whether
potent
(Fig.
cells
evidence
of lymphoid
nlents
mice
shown
to be clonal
eosinophils,
red
of
or
com-
there
to a
con-
ACTIVE’
STEM
CELLS
ERYTHROCYTES
Fig. 1 .
A possible model of the
hematopoietic
stem cell system. Each
cell portrayed
is a stem cell, i.e.,
capable
of self-replication
as well
as differentiation.
The myeloid
system is shown as normally maintained
by three specialized stem cells. There
is a cell pluripotent
for lymphocytes
and myelocytes,
but its exact relation
to the cell pluripotent
for all myeloid
tissue is uncertain.
-
PLATELETS
As discussed in the
text, the exact structure
system is unclear.
of the
entire
A
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DANE
452
clusively
disproved.
erythropoietin-sensitive
a statement
which
knowledge
fairly
For
of
seems
murine
complex
cell
of the
cytes
negate
structure
if CML
to
is a disease
that
CML
potent
for
myeloid
and
lymphoid
thesis
and
undergo
mitosis
or “T”
lymphocytes.
pluripotent
normal
for
as
the
the
lymphocyte
even
peared
was
with
performed,4
CML
The
of chromosomes
from patients
would
and
B”
and
that
“T”
lymphoblastic
surface
in which
myeloid
act
of
defect
is
would
which
is pluri-
enter
DNA
thought
to
is due
to an
be
own
abnormal
replacement
stem
of
cell
many
years
years
that
they
averaging
have
many
in the
may
capable
before
PHA-stimulated
mature
reproduce
in the
occasional
it-
of
undergoing
the
defect
lymphocytes.
lymphocytes
was made
the
for
cell
to divide
a stem
synthymus
be anticipated
suggest
perhaps
as its
CML
cell
cells,
not
of
in lympho-
with
if CML
is induced
studies
there
ap-
Most
re-
from
patients
shortly
before
the
long-term
survivors
be of interest.
hypothesis
CML
are
would
take
conversion
on what many
will consider
to be highly
in Wright’s-stained
smears.
However,
hoped
that
this editorial
will stimulate
“
as
Ph’
which
PHA
in PHA-stimulated
in whom
the diagnosis
similar
the
a stem
even
may
of
pool,
conversion
patients
of T lymphocytes
survival
time,
it might
cell
lymphoblastic
from
to
which
number
stem
Lymphocytes
is a disease
appreciable
ported
studies
with CML
are
study
if CML
murine
involving
well
lymphocyte
differentiation,
in an
a
to find
T cells
at all. Kinetic
studies
long
intermitotic
Furthermore,
lymphocytic
failure
exposed
leukemic
animal;
Thus,
of
reached
cell,
However,
by
“mature”
that
tissue.
when
years.24
self.
state
have
point
in the system
there
is a cell
lymphoid
tissue.
If there
is a similar
is a disease
lymphocytes
T compartment
or perhaps
not
an extraordinarily
current
“We
(PHA)
concept
cell,
of
phytohemagglutinin
the
dependent
the
structure:
of the
that
at some
myeloid
and
be a reasonable
expectation.
it would
seem that the
exposed
suggesting
that
the
Lajtha23
made
G2.22
concerning
compartment
exact
evidence’7
for both
and
CML
would
Superficially,
appropriate
cell
has data
during
of ignorance.”
compelling
is pluripotent
in man
very
stem
state
Independent
fairly
which
example,
Goldwasser
cell is sensitive
primarily
R. B000S
the
characteristics
immature
in
cells
are
of CML
questionable
this hypothesis
an examination
not
the
may
occasional
obviously
occur
is based
data,
appearance
of blasts
can be tested,
and it is
of such
measures
as
blastic
ofmyeloid
conversion
in
origin.
ACKNOWLEDGMENT
I am indebted
ing
me with
to Dr. Carl Srodes,
the
patients
with
Dr. William
possible
lymphoblastic
Cooper,
and
Dr.
Anthony
Haridan
for acquaint-
transformation.
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EDITORIAL
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1974 44: 449-453
Editorial: Hematopoietic Stem Cell Theory in Relation to Possible
Lymphoblastic Conversion of Chronic Myeloid Leukemia
Dane R. Boggs
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Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
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Copyright 2011 by The American Society of Hematology; all rights reserved.