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Analyses
of Phenotype
and
Genotype
in Acute
Presentation
By Anand
As a clue
relapse
to the
we
leukemia
cellular
(ALL)
Blast
and
were
relapse
monoclonal
blots
heavy
fl-chain
gene
T
of respective
light
both
of
Several
of acute
tation
and
relapse
have
relapse,
and
namely
(3)
determine
were
approach
outcome
)
studies.3
and
identical
we could
still
and
poorly
detection
We
phenotype
to
provide
that
at
AND
MATERIALS
evidence
leukemic
leukemic
Using
that
at
this
despite
cells may be related
cell clone.
METHODS
Cell samples
were obtained
from I I ALL patients
who were
undergoing
routine
diagnostic
immunophenotyping
studies
under
protocols
approved
by the Bundesministerium
f#{252}r
Forschung
und
Technologie.4
These patients
were selected
because sufficient
cryopreserved
material
for DNA
extraction
from both initial
diagnosis
and first relapse was available.
Clinical
features
are summarized
in
Table 1 Smears of peripheral
blood and bone marrow were stained
by standard
techniques
including
Wright-Giemsa,
periodic
acidSchiff reagent
(PAS),
myeloperoxidase
(MPO),
acid phosphatase
(AP) and naphtol AS-D chloroacetate
esterase
(CAE), and charac-
.
terized
cation.’
according
Enriched
Ficoll-Hypaque
to the
French-American-British
preparations
gradient
of blast
separation
and
(FAB)
cells
resulted
were
classifi-
obtained
in >90%
blast
by
cells
in all specimens
studied.
Immunologic
phenotypes
were determined
with monoclonal
antibodies
BI, B4, iS (Coulter
Immunology,
Hialeah, FL), Leu9 (Becton Dickinson,
Sunnyvale,
CA), OKT3, OKT6,
OKTI 1, OKIa (Ortho Pharmaceutical
Corp, Raritan,
NJ), BA-I,
BA-2 (Hybritech
Incorp, San Diego) and VIM-2 (generously
provided by Dr W. Knapp, Vienna).
Binding of monoclonal
antibodies
to targets was assessed
by indirect
immunofluorescence
procedures
as described.6
The presence of terminal
deoxynucleotidyl
transferase
(TdT) was examined
by indirect
immunofluorescence
as described
by Bollum.7
DNA was extracted
from cryopreserved
leukemic cell samples by
standard
techniques.
Fifteen micrograms
DNA was digested
with
appropriate
restriction
enzymes
(Boehringer
Mannheim),
electrophoresed
on 0.7% agarose gel, blotted and hybridized
as described.8
X-DNAs were included
as molecular
weight standards.
To demonstrate Ig-gene rearrangements,
BamHI
digests were hybridized
to a
1.3 kb EcoRI CM probe, which detects a 17-kb germline
band9 (Fig
IA) and a c-k probe, which detects a 12-kb germline band in BamHI
Blood,
Vol 70, No4
(October),
1987:
pp
1079-1083
and
results
order
relapsed
the
unravel
the
disand
with
value
nature
T$
a very
configuration
emphasize
to
phenotype
but
germline
exhibited
in recurrent
T-ALL
diagnosis
for
T/9
of
molecular
of
leukemic
relapse.
S
1987
by Grune
& Stratton,
Inc.
(Fig I B). Both probes were kindly provided by Dr P. Leder.
and BamHI digests were hybridized
to a CT3 probe detecting
12-kb and 4.2-kb germline
bands.8 (Fig lC) After hybridization,
the
filters were washed
under
stringent
conditions
and exposed
to
XAR-5
film (Kodak)
using Dupont
Lightning-Plus
intensifying
screens for up to 24 hours at
70#{176}C.
-
RESULTS
to
cells
diagnosis.
phenotype
Our
at diagnosis.
sequences
both
germline
ALL
analyses
in malignant
compelling
a similar
phenotype
at relapse,
but not identical
to the original
in cell
I I
at
in
with
EcoRI,
anal-
molecular
gene
displayed
rearrangement
in
sequences
T/9
patient
populations
presenting
digests9
the patho-
investigated
and
patient,
in
understood.
chromosomal
Another
analyses
Ig
ie,
clone
of shifts
comparative
immunological
if genotype
relapse
(I
(2)
G-6-PD
combining
variations.
of
sequences.
of
leukemic
(ALL)
of T/9 gene
immature
receptor
cell
ease.
gene
been used to study
the relationship
leukemia
(ALL)
cells at first presen-
phenotypes,’
patients
hybridized
were
leukemic
are
of
comparison
clonal
novel
identical
pre-T
a rearrangement
a variety
T-ceII
beside
One
configuration
diagnosis
at First
and Claus R. Bartram
states.
phenotypes
cases,
in clinical
of leukemia
techniques
lymphoblastic
membrane
yses,’
or
relapse
to immunoglobu-
as to
similar
revealed
evoluted
DIFFERENCES
genesis
samples
nine
in
genetic
initial
we
as well
While
states
of an
HE
both
using
cell
chain
rearrangements
appearance
molecular
from
simultaneously
sequences.
in
and
obtained
Thiel,
lymphoblastic
Leukemias
in Relapse
Eckhard
populations
acute
immunophenotyped
and
(Ta)
observed
of
and
Raghavachar,
of leukemic
cases
immunological
cells
antibodies;
Southern
(Ig)
11
by
approaches.
un
origin
analyzed
Lymphoblastic
Immunological
examination.
All patients
were classified
as
having acute lymphoblastic
leukemia
based on lymphoid
morphologic appearance
and negative
staining
for MPO. The results of
immunological
cell marker
studies at the time of diagnosis
and at
relapse
are given in Table
2, following
criteria
reported
elsewhere.’#{176}”At first examination,
seven patients
presented
with common ALL, two with pre-T ALL (TdT+,
Leu9+,
TI 1 -, T6-,
T3 - ), one with 1-ALL
and one showed
acute undifferentiated
leukemia
(AUL).
Reassessment
of leukemia cell phenotypes
at relapse revealed that
the immunological
diagnoses
were close to the initial
subtype.
However,
within
a given
subtype,
some
minor
shifts
of the
marker
pattern in relapse were detected
in three patients.
The phenotype
of
pre-T ALL cells in patient
no. 10 changed
from TdT+
to TdTand, in addition,
the cells became HLA-DR
antigen positive. Patient
no. 2 (cALL)
had a 35% reduction
in the proportion
of the cells
positive for anti-BI
monoclonal
antibody
at the time of relapse.
In
patient
no. 9, initially diagnosed
as having pre-T ALL, an incomplete, more mature T cell phenotype
(T6 + , T3 + , TI I - ) developed
in recurrent
disease. Another
shift was observed in patient no. 8 who
appeared
to have a I cell phenotype
at presentation
and a pre-T
phenotype
in relapse.
From
University
and
the Department
of
Ulm,
Medizinische
Submitted
Supported
Address
ment
of Transfusion
FRG
Klinik
January
by the
Ulm,
The publication
charge payment.
“advertisement”
1987;
Deutsche
reprint
requests
Medicine,
Medicine
Institute
lnnenstadt,
26.
of Transfusion
10, D-7900
and
and
Pediatrics
of Hematology
University
accepted
June
of the
ofMunich,
II,
GSF
FRG
6, 1987.
Forschungsgemeinschaft.
to Anand
Raghavachar,
University
ofUlm.
MD,
Oberer
DepartEselsberg
FRG.
costs ofthis
This article
in
accordance
article
must
with
were defrayed
in part by page
therefore
be hereby
marked
18
U.S.C.
§1734
solely
to
indicate this fact.
©
1987
by Grune
& Stratton,
Inc.
0006-4971/87/7004-0003$3.OO/O
1079
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
RAGHAVACHAR,
1080
Table
1 . Clinical
Age
(yr)/Sex
Patient
No.
Features
Time
Presentation
in 1 1 ALL
From First
to Relapse
22/F
2
28/M
3
64/F
4
5
#{149}1
H
cALL
C,.,
i3455
H:
1
H
E
3
cALL
19/M
14
cALL
5
24/F
24
CALL
6
17/M
4
cALL
cALL
E
B
6/M
16
8
8/M
6
9
5O/M
17
pre-T-ALL
10
29/M
30
pre-T-ALL
11
34/F
T-ALL
5
K
I
12345
Hkd
?C
E
E
Barn
dc
Immunological
a
b
a
TdT
+
+
BA-i
+
+
BA-2
-
84
+
Bi
-
J5
+
OKIa
+
+
Data
of 1 1 ALL Patients
3
4
b
a
b
a
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
-
+
-t
+
+
+
+
+
C
Ban
.
EcoRl
EcoRl
D0.i
C,_,
HI
Studied
During
Presentation
6
(a) and in Relapse
7
8
a
b
a
b
a
b
a
b
a
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
-
-
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
OKT11
+
staining
cells were
in
indirect
38%
in
10
b
+
20%
immunofluorescence
(a) and 5% in (b).
assays.
Ck (B)
in the
(b)
9
a
OKT6
>
HI
ing germline
Ig-heavy-chain
sequences
at both disease states, examination ofTf. genes was informative;
this pre-T ALL lacked Tfl-gene
rearrangements
initially; however,
at relapse, a Tf gene rearrangement was visible (Fig 4). As mentioned
above, blast cells of this state
had become TdT-negative,
retained
a Leu9+
phenotype,
but lacked
more mature T cell markers.
Thus, there was a discrepancy
between
the genotype
and cell surface marker expression.
On the other hand,
in patient
no. 8 in accordance
with phenotypic
conversion
from T- to
pre-T-ALL,
the genotype
changed
from rearranged
to germline
configuration
of T9-chain
sequences.
These results are in concordance with the respective
phenotypes
of the leukemic cells, with the
remarkable
exception
of case no. 9 presenting
a I cell leukemia
by
immunological
criteria
but displaying
rearrangements
of both T/3
and lg sequences.
Although
this patient exhibited
a more mature I
cell phenotype
at relapse, Southern
blot analyses
showed identical
+
positive
2
Sam
b
VIM-2
EcoRl
C,.
.
.--‘
OKT3
tBl
J1.2
-c:::1---4B-LITJ
00
.
EcoRl
D,.2
Fig 1 .
Restriction
map of human
germline
JH-Cs (A).
and TCR (C) Ioci. Fragments
used as probes
are indicated
lower part of the map. H. Hindlll;
E, EcoRl.
5
Leu9
. +
Probe
1 kb
,
2
E
11Jj
AUL
the clonal relationships
between
respective
leukemia
we compared
Southern
blot analyses
of both
disease
states
(Fig
2). Of the 1 1
patients
studied,
nine showed a rearrangement
of Ig-heavy-chain
gene sequences
(patients
no. 1 to 7, 9, and I I ). Identical
rearranged
bands at initial presentation
and relapse were detected
in four cases
(patients
no. I 3, 4, and 7). Different
patterns
of Ig-rearrangements
in both disease
states were detected
in five patients.
At initial
diagnosis,
Southern
blot analyses
revealed a rearrangement
of both
heavy-chain
alleles in patient no. 2. However,
in recurrent
disease
the larger fragment
of one allele was only very faintly visible. We
interpret
this hybridization
pattern as an indication
for a deletion of
Ct sequences
from one allele in the leukemic
population
in relapse;
the faintly hybridizing
band suggests
the concurrent
persistence
of
the initial leukemic clone at a very low percentage.
Additionally,
it is
remarkable
that we observed
a reduced
proportion
of BI-positive
cells at relapse. In patients no. 6 and 1 1 , the loss of the germline
band
in recurrent
disease also indicates
an additional
deletion
affecting
one allele at this state while the other allele shows the same
rearranged
band. In contrast,
in patients
no. 5 and 9, Southern
blot
analysis
revealed
Ig rearrangements
at relapse that could not be
observed
in the initial state. Moreover,
different
kappa-light-chain
rearrangements
were detected
in patient no. 5 at both states (Fig 3).
In patient
no. 6, kappa-light
chains were deleted at both instances.
Faintly hybridizing
bands of germline
size in this case represent,
in
all likelihood,
contamination
of cell samples with no leukemic
cells.
In all other
patients
studied,
kappa-light-chain
sequences
were in
germline
configuration
(data not shown). In patient no. 10, exhibit2.
8
12kb
I
Bm
-
In order to establish
initial
and relapsed
Table
8
CP,ob.
7
1
8
t::j
HI
cALL
24
DNA-analysis.
BARTRAM
A:
Immunological
Diagnosis
at
Presentation
(mo)
AND
17kb
,4
Patients
THIEL,
+
+
11
a
b
+
+
+
+
+
+
+
+
-
-
+
-
-
+
-
-
+
+
+
+
b
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHENOTYPE
AND
GENOTYPE
IN ThE
COURSE
OF ALL
1081
I
2
AB
AB
3
4
AB
A
.
_
5
B
A
6
B
A
B
.,
.
.
-17kb
:
--‘
H
7
8
ABAB
9
10
11
AB
AB
k.B.
N
!.,1
17kb
;
.
Fig 2. Southern
blot analyses
of DNAs
(1 5 big) obtained
from leukemic
cells of 11
ALL patients
at first presentation
(A) and
relapse
(B). BamHl
digests
were
electrophoresed.
blotted,
and hybridized
to a
Ca-probe
that detects
a 1 7-kb germline
autoradiographic
band.
N = placentacontrol
DNA.
Tfl rearrangements
in both disease states (Fig 4), while the pattern
of Ig rearrangements
was entirely
different
(Fig 2) as outlined
above. With these three exceptions,
in the remaining
patients
1-fl
genes were in germline configuration
at both instances
(not shown).
We
have
patients
reassessed
tumor
in order
5
A
B
cell
pheno-
to establish
6
the
AB
N
and
clonal
genotypes
-,
the
in I I
immunological
remained
8
relationships
subtype
virtually
in
identical
the
10
A
B
.
:
-12
L:
PL4.2
:.
Fig 3.
Configuration
of kappa-light-chain
sequences
in
patients
no. 5 and 6. BamHI digests were electrophoresed.
blotted.
and hybridized
to a c-k probe
that
detects
a 1 2-kb
germline
fragment.
of
diagnosis
ALL
and
9
AB
-
majority
at initial
ABC
kb
w
.
that
patients
DISCUSSION
ALL
between
initial
and relapsed
disease.
These patients
included
different
immunological
ALL
subtypes.
Relapses
occurred
within
3 and 30 months
ofdiagnosis.
Our study demonstrates
kb
$
.-‘
-12
-42
L5
Fig 4.
Configuration
of T cell receptor
fl-chain
sequences
in
patients
no. 8. 9. and 10 at first presentation
(A) and relapse
(B).
EcoRI
digests
were
electrophoresed.
blotted.
and hybridized
to
CT/9 sequences
that
detect
12-kb and 4.2-kb
germline
bands. N =
placenta-control
DNA.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
RAGHAVACHAR,
1082
relapse.
This
patients.”
is supported
by previous
However,
in former
and Tf3-gene
rearrangements
determining
the ultimate
have not been performed.
detected
marked
at diagnosis
and
Southern
blot
heterogeneity
relapse.
Seven
tumors,
irrespective
late relapses.
The
evolution
tion rather
suggested
ranged
allele
rule
within
no.
of different
a single
cell clones
patients
those
found
these
patients
our findings
the
and
relapse
possibility
novel leukemic
cell clone
ct and c-k rearrangements,
population
persisted
monoallelic
explanation
to the use of a common
identical
rearranged
popula-
evidence
for
clone in ALL
leukemic
related.
relapse
We
of this
cjt and
might
a
by distinct
leukemic
visible
c-k sequences.
be of interest,
the presence
of more
at first presentation’#{176}”
cannot
In this
providing
strong
than
one leukemic
cell
or relapse.’4
The clonal
relationship
in patients
no. 8 and 10 cannot
be sufficiently
settled
by our molecular
genetic
studies
since these patients
shared
no identical
gene rearrangements
at both instances.
In principal,
cytogenetic
instances
but
In a recent
were unavailable
report
cytogenetic
diagnosis
to relapse
revealed
analyses
might
be of help
leukemic
clone.
Studies
of independent
of G-6-PD
support
this
in patient
pre-T-ALL
pheno-
both
at
leukemic
questions
rearrangement
recombinase
TCR
sequences
may
relapse)
show
the
populations
but
raise
concerning
the
regulation
rearrangements
may
remain
clonal
of
TCR
genes during
the early stages
of lymphocyte
tiation.
In such situations
recombinases
responsible
TCR-gene
be
in B and T cells.’8
(but completely
some
Ig and
differenfor Ig
active
until
mature
Ig or ICR
molecules
are produced.
In this respect,
the molecular
mechanism
for the Ig-gene
variation
detected
at relapse
may
In summary,
include
normal
developmental
progression.
recognition
of changes
in Ig- and Tfl-gene
our
t the time
understanding
and of the
populations.
of the
of leukemic
pathogenesis
relapse
of tumor
may
increase
recurrence
selective
effects
of therapy
on neoplastic
This study
represents
a first step toward
goal. Investigation
sequence
analyses
and
of
follow-up
respective
cell
this
of more patients
(including
rearranged
TCR
and
genes)
may, therefore,
finally
reveal
the clinical
of the molecular
differences,
ie, clonal
evolution
dent clones among
these patients.
Ig
importance
of indepen-
phenotypes
ACKNOWLEDGMENT
from
cell
clones
in two of 51 ALL patients.’
In this context,
our data
might
provide
support
for the view that leukemic
cells of
some cases in relapse
may be related
but not identical
to the
original
The
BARTRAM
in such
for our cases.
analyses
of changes
the presence
interest.
rearrangements
of
rearrangements
by
et al’6 further
rearrangements
for this cross-lineage
Ig
interesting
and
at
patient
evolved,
different
relationship
the
cells
molecularly
affecting
reports
I 1 . However,
in patient
clonally
be of particular
AND
type of this patient
at diagnosis
is in keeping
with the recent
notion
that patients
with precursor
I cell leukemia
show a
greater
tendency
to rearrange
both Ig and TCR
genes.”7
due
The
that
in the
no. 9 might
The
had early
or
may reflect
the
emerged
characterized
while
the original
but
deletions
recent
are
that
lymphoma
by Fialkow
In this context,
the dual
on initial
rearrangements
to establish
Burkitt’s
notion.
exhibited
malignant-cell
2, 5, 6, and
kappa-gene
it difficult
diagnosis
out
respect,
with
of whether
possibility
that
in cases
5 makes
initial
of Ig
than the occurrence
of two independent
clones
is
by the detection
of at least one identical
rear-
discovery
no.
on more
of leukemic
of eleven
discordant
of subclones
based
examination
as a convenient
method
for
clonality
of lymphoid
neoplasms
Indeed,
using
this approach
we
clonal
analyses
studies
studies,
THIEL,
in
We thank
Monika
Blum and Monika
Dodrimont
for expert
technical
assistance,
Bernhard
Kubanek
and Enno Kleihauer
for
continuous
support,
as well as Heidi Barro for preparation
of this
manuscript.
This paper is dedicated
to Professor
E. Kleihauer
on the
occasion of his sixtieth birthday.
REFERENCES
I . Borella C, Casper
iT, Lauer SJ: Shifts in expression
of cell
membrane
phenotypes
in childhood
lymphoid
malignancies
at
relapse. Blood 54:64, 1979
2. Williams
DL, Raimondi
SC, Rivera G: Most cases of acute
lymphoblastic
leukemia
(ALL)
undergo
marked
karyotypic
shift
from diagnosis
to relapse. BlOOd 64:208a,
I 984 (suppl 1)
3. Dow LW, Martin P. Moohr J, Greenberg
M, Macdougall
LG,
Najfeld
V, Fialkow
Pi: Evidence
for clonal development
of childhood acute lymphoblastic
leukemia.
Blood 66:902, 1985
4. Hoelzer
D, Thiel E, L#{246}ffier
H, Bodenstein
H, Plaumann
L,
Bflchner Th, Urbanitz
D, Koch P. Heimpel H, Engelhardt
R, MUller
U, Wendt
FC, Sodomann
H, RUhI H, Hermann
F, Kaboth
W,
Dietzfelbinger
H, Pralle H, L#{228}nschkenCh, Hellriegel
KP, Spors S.
Nowrusian
M, Fischer i, FUller HH, Mitron
P. Pfremdschuh
M,
Gorg Ch, Emmerich
B, Queisser W, Meyer P. Labedzki
L, Essers U,
Konig H, Mainzer
K, Fritze D, Messerer
D, Zwingers
Th: Intensifled therapy
in acute
lymphoblastic
and acute undifferentiated
leukemia
in adults. Blood 64:38, 1984
5. Bennett
iM, Catovsky
D, Daniel
MI, Flandrin
G, Glaton
DAG, Gralnick
HR, Sultan C: Proposals
for the classification
of
acute
leukemias.
French-American-British
(FAB)
Cooperative
Group. Br J Haematol
33:451, 1976
6. Thiel E, Kummer
U, Rodt H, StUnkel K, Munker
R, Majdic
0, Knapp
W, Thierfelder
5: Comparison
of currently
available
monoclonal
antibodies
with conventional
markers
for phenotyping
of
one hundred
acute leukemias.
Blut 44:95, 1982
7. Bollum Fi: Terminal
deoxynucleotidyl
transferase
as a hematopoietic cell marker.
Blood 54: 1203, 1979
8. Raghavachar
A, Bartram
CR, Kubanek
B: Immunoglobulin
and I cell receptor gene rearrangements
in human acute leukemias,
in Baum Si, Pluznik
DH, Rosenszajn
LA (eds): Experimental
Hematology
Today 1985. Berlin, Springer-Verlag,
1986, p90
9. Bakhshi
A, Minowada
J, Arnold A, Cossman
G, iensen iP,
Whang-Peng
i, Waldmann
TA, Korsmeyer
Si: Lymphoid
blast
crises of chronic
myelogenous
leukemia
represent
stages
in the
development
of B-cell precursors.
N Engl J Med 309:826,
1983
10. Raghavachar
A, Bartram
CR, Ganser A, Heil G, Kleihauer
E, Kubanek
B: Acute undifferentiated
leukemia
(AUL):
Implications for cellular origin and clonality suggested
by analysis of surface
markers
and immunoglobulin
gene rearrangement.
Blood 68:658,
1986
1 1 . Thiel E, Rodt H, Thierfelder
5: Leukemic
cell phenotypes
and the lymphoid
differentiation
pathway.
Haematologica
66:389,
1981
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
PHENOTYPE
AND
GENOTYPE
IN THE COURSE
OF ALL
12. Van Dongen iJM, Quartermous
I, Bartram
CR, Gold DP,
Wolvers-Tettero
ILM,
Comans-Bitter
WM,
Hooijkaas
H,
Adriaansen
Hi, de Klein A, Raghavachar
A, Ganser A, Duby AD,
Seidman
iG, van den Elsen P. Terhorst
C: The I cell receptor
CD3
complex during early I-cell differentiation:
Analysis of immature
I
cell acute lymphoblastic
leukemias
(I-ALL)
at DNA, RNA, and
cell membrane
level. J Immunol
138:1260,
1987
13. Kitchingman
GR, Mirro G, Stass S. Rovigatti
U, Melvin SL,
Williams
DL, Raimondi
SC, Murphy
SB: Biologic and prognostic
significance
of the presence of more than two is-heavy chain genes in
childhood
acute lymphoblastic
leukemia
of B-precursor
cell origin.
Blood 67:689,
1986
14. Zehnbauer
BA, Pardoll DM, Burke Pi, Graham
ML, Vogelstein B: Immunoglobulin
gene rearrangements
in remission
bone
marrow specimens
from patients with acute lymphoblastic
leukemia.
Blood
67:835,
1986
1083
15. Pelicci PG, Knowles DM, Dalla Favera R: Lymphoid
tumors
displaying
rearrangements
of both immunoglobulin
and I cell
receptorgenes.
J Exp Med 162:1015,
1985
16. Fialkow PJ, Klein E, Klein G, Clifford P. Singh 5: Immunoglobulin
and glucose-6-phosphate
dehydrogenase
as markers
of
cellular origin in Burkitt’s
lymphoma.
i Exp Med 183:89, 1973
17. Davey MP, Bongiovanni
KF, Kaulfersch
W, Quertermous
I,
Seidman
iG, Hershfield
MS. Kurtzberg
i, Haynes BF, Davis MM,
Waldmann
TA: Immunoglobulin
and I cell receptor
gene rearrangement
and expression
in human
lymphoid
leukemia
cells at
different
stages of maturation.
Proc NatI Acad Sci USA, 83:8759,
1986
18. Yancopoulos
GD, Blackwell
1K, Suh H, Hood L, Alt FW:
Introduced
I-cell receptor variable region gene segments
recombine
in pre-B cells: Evidence
that B and I cells use a common
recombinase. Cell 44:251, 1986
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1987 70: 1079-1083
Analyses of phenotype and genotype in acute lymphoblastic leukemias at
first presentation and in relapse
A Raghavachar, E Thiel and CR Bartram
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