1. Art and Diseño

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Formation of a Hyperdiploid Karyotype in Childhood Acute Lymphoblastic
Leukemia
By Norio Onodera, Norah R. McCabe, and Charles M. Rubin
Hyperdiploidy with 250 chromosomes is a frequent and
distinct karyotypic pattern in the malignant cells of children
with acute lymphoblastic leukemia. To understand better the
mechanism of formation of the hyperdiploid karyotype, we
studied 15 patients using 20 DNA probes that detect restriction fragment length polymorphisms. We first examined
disomic chromosomes for loss of heterozygosity. Two patients had widespread loss of heterozygosity on all informative disomic chromosomes, and represent cases of nearhaploid leukemia in which the chromosomes doubled. One
other patient had loss of heterozygosity limited t o chromosome 3; in this patient all of seven other informative disomic
chromosomes retained heterozygosity. Loss of heterozygosity was not detected in the remaining 12 patients on a total of
87 informative disomic chromosomes. We then examined
tetrasomic chromosomes for parental dosage. Of the 13
patients in whom widespread loss of heterozygosity was not
present, 11 patients had tetrasomy 21; 10 of 11 (91%) had an
equal dose of maternal and paternal alleles on chromosome
21 and only 1 of 11 (99’0) had an unequal dose of parental
alleles in a 3:l ratio. These results suggest that the hyperdiploid karyotype usually arises by simultaneous gain of chromosomes from a diploid karyotype during a single abnormal
cell division, and occasionally by doubling of chromosomes
from a near-haploid karyotype. The hyperdiploidy in cases
without widespread loss of heterozygosity is not caused by
stepwise or sequential gains from a diploid karyotype or by
losses from a tetraploid karyotype; the former should result
in a 3 : l parental dosage for 67% of tetrasomic chromosomes
(9% observed) and the latter should result in loss of heterozygosity for 33% of disomic chromosomes (1% observed).
Additional studies of the molecular basis for this leukemia
subtype are warranted.
0 1992by The American Society of Hematology.
A
tion of a chromosomal homologue containing a specific
mutation that provides the cell with a proliferative advantage in a dose-dependent manner. This hypothesis invokes
the presence of independent mutations on each of the
affected chromosomes. Alternatively, a single mutation or a
single carcinogenic event may lead to the hyperdiploid state
as a secondary effect. Finally, a gene mutation may not be
critical to the development of hyperdiploidy; instead, the
gain of certain chromosomes may enhance proliferation of
early lymphoid cells through a change in dosage or relative
dosage of a set of genes.
Here we report 15 patients with hyperdiploid ALL with
> 50 chromosomes including two patients reported previ0us1y.~~
We used restriction fragment length polymorphisms to address the pathophysiology of the disease. We
provide strong evidence to support the view that the
hyperdiploid karyotype occurs as a sudden gain of multiple
chromosomes.
HYPERDIPLOID karyotype is observed in 23% to
42% of newly diagnosed children with acute lymphoblastic leukemia
These patients are generally
divided into two subgroups, namely, those with a chromosome number of 47 to 49 and those with >50 chromosomes.
The hyperdiploidy 2 50 group has a nonrandom pattern of
chromosomal gain. Nearly all of the patients have a
chromosome number of 51 to 65 with a peak at 55.7
Frequently gained chromosomes (in more than half of the
cases) are chromosomes 4, 6, 10, 14, 17, 18, 20, 21, and X,
and rarely gained chromosomes (less than 10% of the
cases) are chromosomes 1, 2, 3, 12, and 16.8Typically, the
affected chromosomes are present in three copies (trisomic). However, chromosome 21, the most frequently
gained ~ h r o m o s o m e , often
~ ~ 3 ~is~tetrasomks
~~
The presence of hyperdiploidy > 50 correlates strongly
with good risk features, including age between 3 and 7 years
old, white blood cell (WBC) count less than 10 X 109/L,
French-American-British (FAB) Cooperative Group subtype L1,l and common ALL antigen (CALLA, CD10)
positive early pre-B p h e n ~ t y p e .Patients
~
with hyperdiploidy 2 50 have the longest disease-free survival compared
with any other cytogenetic group.1°
Recently, we reported two cases of childhood ALL with
hyperdiploidy > 50 in whom the hyperdiploid leukemic
clone arose from a near-haploid clone through doubling of
the chromosomes.ll We verified this mechanism by demonstration of widespread loss of heterozygosity on all disomic
chromosomes (chromosomes present in two copies). However, in the majority of cases of hyperdiploid ALL, the
mechanism leading to the increased number of chromosomes is unknown. Possibilities include development of
tetraploidy with subsequent loss of chromosomes, gains of
individual chromosomes in a stepwise or sequential fashion,
or simultaneous gain of multiple chromosomes in a single
abnormal cell division.
Also, unknown is the biologic significance of hyperdiploidy to the leukemic process.12 The extra chromosomes
may result from selection for cells undergoing nondisjuncBlood, Vol80, No 1 (July 1). 1992: pp 203-208
MATERIALS AND METHODS
Patients. All patients were children with ALL and a hyperdiploid karyotype with 2 5 0 chromosomes. The patients were se-
From the Depa rtments of Pediatiics and Medicine, University of
Chicago, Chicago, IL; and the Children’s Medical Center, Iwate
Prefectural Kitakami Hospital, Kitakami, Iwate, Japan.
Submitted January IO, 1992; accepted March 3, 1992.
Supported in part by Grant CA42557 (to Dr. Janet D. Rowley) from
the National Institute of Health and Grant DE-FG02-86ER60408 (to
Dr. Janet D. Rowley) from the Department of E n e w . C.M.R. is a Pew
Scholar in the Biomedical Sciences.
Address reprint requests to Charles M. Rubin, MD, Department of
Pediatrics, University of Chicago, 5841 S Maryland Ave, MC 4060,
Chicago, IL 60637.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1992 by The American Society of Hematology.
0006-4971I92 I8001 -0002$3.00 10
203
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ONODERA, McCABE, AND RUBIN
204
lected on the basis of availability of cryopreserved leukemic bone
marrow containing 2 85% blasts. One patient (patient 6) had only
61% blasts in the leukemic sample. Features of the patients are
shown in Table 1. Twelve patients were studied at diagnosis and
three patients (patients 4, 6, and 10) were studied at relapse. Two
patients (patients 2 and 6) were reported in a previous publication" and are investigated further in this study.
Cytogenetic analysis. Cytogenetic analysiswas performed using
a trypsin-Giemsa banding technique. Cells were obtained from
bone marrow and/or peripheral blood before initiation of chemotherapy. Metaphase cells from direct preparations and/or shortterm (24 and 48 hours) unstimulated cultures were examined.
Chromosomal abnormalities were described according to the
International System for Human Cytogenetic N0menc1ature.l~
Molecular analysis. DNA was extracted from clyopreserved
buRy coat cells from bone marrow at diagnosis or relapse of
leukemia. In eight patients (patients 1, 2, 5, 6, 11, 12, 14, and 15)
DNA was extracted from fresh mononuclear cells of peripheral
blood or cryopreserved buRy coat cells from bone marrow during
complete remission; this nonleukemic material represented constitutional DNA. Restriction endonuclease digestion, electrophoresis, Southern blotting, radiolabeling of probes, and DNA hybridization were performed according to standard procedures.
Informative probes were those showing two different alleles. In
patients in whom we did not have a sample of nonleukemic DNA,
we could not distinguish between a noninformative probe and loss
of heterozygositywhen only one polymorphicband was observed.
Densitometry was used to quantify the intensity of bands on
exposures of Southern blots. Densitometly was performed by
transmittal of the image to a computer using a CCD camera CX-77
(SONY, Tokyo, Japan) and the program MacVision (Koala Technologies, Morgan Hill, CA). The image was analyzed further by the
program Densitometly on a Disk (Amoco Corporation, Naperville,
IL). When quantifying the intensity of bands for VNTR (variable
number of tandem repeats) probes, a mathematical correction was
made.14 The intensity of lower bands in the autoradiogram were
corrected by the following formula: lower band intensity x upper
band size/lower band size.
Probes. The 20 probes used to detect DNA restriction fragment
length polymorphismsare described in Tables 2 and 3. Additional
information and references are listed in the report of the 10th
International Workshop on Human Gene Mapping.15Probes p2.1,
p21-4U, pG95-al-lla, and pPW228C were gifts from Drs Ellen
Solomon, Gordon D. Stewart, Bradley N. White, and Integrated
Genetics (Framingham, MA), respectively. Probes CRI-R59 and
CRLL427 were purchased from Collaborative Research Inc (Bedford, MA). The remaining probes were obtained from the American Type Culture Collection (ATCC; Rockville, MD). Probes
pMCT118, cYNA13, pYNH24, pTBAB5-7, pEFD64.1, pJCZ67,
pMHZ10, pCMM6, and pMCT15 were deposited at ATCC by Drs
Ray White and Yusuke Nakamura. Probes pCMW-1, p79-2-23,
pGSH8, and 26C and p21.3 were deposited by Drs David Ledbetter, Michael Litt, Gordon D. Stewart, and A. Millington-Ward,
respectively.
RESULTS
Karyoypes. The results of cytogenetic analyses are described in Table l. All 15 patients had one or more
abnormal clones with 50 to 60 chromosomes. Thirteen
patients had typical hyperdiploidy in which most of the
affected chromosomes were present in three copies (trisomic), and two patients (patients 2 and 6) were atypical
because nearly all affected chromosomes were tetrasomic.
All 15 patients had extra copies of chromosomes 21 and X.
Extra copies of chromosomes 4, 6, 10, 14, 17, and 18 were
observed in more than 10 of the patients. Thirteen patients
had tetrasomy 21 (patients 1 through 13). Some chromosomes were not gained in any of the cases including
chromosomes 1, 2, 3, 7, 15, and 16; thus, these chromosomes were always disomic. Fourteen of 15 patients were
disomic for chromosomes 9,11,13,19, and 20.
Structural abnormalities were observed in five patients.
Two patients (patients 3 and 9) had partial duplication of
the long arm of chromosome 1, one patient (patient 10) had
Table 1. Cytogenetic Studies of 15 PatientsWith ALL and a Hyperdiploid Karyotype
Sex
State of
Disease
No. of Metaphase
Cells Examined
4
5
7
M
F
F
Diagnosis
Diagnosis
Diagnosis
33
32
33
4
5
3
10
F
F
Relapse
Diagnosis
31
22
6t
7
8
9
18
3
18
3
M
M
F
M
Relapse
Diagnosis
Diagnosis
Diagnosis
21
12
22
20
10
9
M
Relapse
21
11
12
13
14
15
1
2
3
2
2
M
M
M
M
M
Diagnosis
Diagnosis
Diagnosis
Diagnosis
Diagnosis
12
13
19
11
26
Patient
Age
(yrs)
1
2'
3
*Reported as Patient 1 in reference 11.
tReported as Patient 2 in reference 11.
Karotypes
46,XY (85%)/56,XY,+X,+4,+5,+6,+ 14,+ 17,+ 18,+21,+21,+22 (15%)
46,XX (81%)/50,XX,+ 18, 18, 21, +21 (19%)
46,XX (18%)/54,XX,+X.+4,+6,+14,+17,+18,+21,+21
(6l%)/
55,XX,+X,+4,+6,+ 14,+ 17,+ 18,+ 19,+21,+21 (12%)/
56,XX,+X,+4,+6,+ lo,+ 14,+ 15,+ 17,+ 18,+21,+21, dup(l)(q21 + q44) (9%)
46,XX (3%)/56,XX,+X,+4,+6,+8,+10,+14,+18,+18,+21,+21
(97%)
46,XX (41%)/54,XX,+X,+4,+12,+14,+17,+18,+21,+21
(55%)/
55,XX,+X,+4,+ 12,+ 13,+ 14,+ 17,+ 18,+21,+21 (4%)
46,XY (90%) 60,XY. +X,+Y,+5,+5,+8,+8,+9,+9,+14,+14,+19,+20,+21,+21
(10%)
46,XY (58%)/56,XY, +X, +Y,+4,+6,+ I O , 14,+ 17, 18, 21, 21 (42%)
46,XX (32%)/56,XX,+X,+4,+6,+10,+14,+17,+18,+21,+21,+mar(68%)
46,XY (30%)/55,XY,+X,+4,+6,+10,+14,+17,+18,+21,+21,d~p(1)(q21 + q32)(40%)/
56,XY,+X,+Y,+4,+6,+10,+14,+17,+18,+21,+21,dup(1)(q21
+ q32) (30%)
46,XY (81%)/55,XY,+X,+4,+5,+6,+14,+14,+17,+18,+12,+21,del(12)(p11p12),dic(21;
21)( pl3; p l 3 ) (19%)
46,XY (50%)/54,XY, +X,+6,+ 13, 14, 17,+ 18, 21, +21 (50%)
46,XY (46%)/60,XY,+X,+4,+5,+6,+8,+10,+11,+12,+14,+17,+18,+21,+21,+22
(54%)
53,XY,+X,+4,+6,+14,+21,+21,+1nar
(100%)
46,XY (45%)/56,XY,+X,+4,+6.+8,+10,+14,+17,+18,+21,+22
(55%)
46,XY (88%)/53,XY,+X.+Y,+6,+14,+
17,+ 18,+21 (12%)
+ +
+ + +
+
+ +
+
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FORMATION OF A HYPERDIPLOID KARYOTYPE
205
Table 2 Analysh of DNA Polymorphhs on Dlsomk Chromosomes In 15 PatientsWith AU and a HyperdiploidKarotype
Maintenanceor Loss of Heterozygosityin Leukemic DNA
Probea
Patient
MaP
Location
Locus
Symbol
Name
1
2
3
4
5
6
IP
lq
2P
2pterq32.3
3pter-p21
3q
7q
9q
llp13-pl5
15pter-q13
16q24
2oq
DlS80
DlS74
D2S47
D2S44
D3S12
D3S42
078396
D9Sll
DllS150
D15S24
D16S7
D20S19
pMCTl18.
cYNA13.
pTBAB5-7.
pYNH24'
CRI-R59
pEFD64.1'
pJCZ67.
CMHZlO'
~2.1'
pCMW-1.
p79-2-23.
pCMM6.
M
M
M
M
M
M
NI
L
M
M
M
M
M
M
M
L
L
L
L
L
L
NI
T
L
NI
L
T
M
M
M
M
M
M
-
M
L
L
NI
L
L
L
L
L
NI
M
M
M
M
NI
-
NI
M
M
M
M
-
M
M
M
M
M
M
M
M
M
M
M
M
M
M
7
8
9
-
1
0
-
-
M
M
M
-
M
M
M
M
M
-
-
M
M
M
M
-
-
M
M
-
M
M
M
M
1
1 2 1 3 1 4
15
NI
M
NI
M
NI
NI
M
M
M
M
M
M
NI
M
M
M
L
L
M
M
M
NI
M
M
M
M
M
M
M
M
M
NI
M
M
M
M
M
M
NI
M
NI
M
NI
M
M
M
-
-
M
M
M
M
M
-
1
M
M
M
-
M
M
M
M
NI
M
T
M
M
M
M
M
M
M
Abbreviations: M, maintenance of heterozygosity; L, loss of heterozygosity; NI, not informative; T, trisomic or tetrasomic, not evaluated; -,
unknown because of lack of availability of constitutional nonleukemic DNA or not tested.
VNTR probe.
Table 3. Analysh of DNA Polymorphlrmson Chromosome 21 In 13 PatientsWith A U and a HyperdlploldKaryotwe Associated With
Tetrasomy 21
Contributionof ParentalAllele8
Probes
Patient
Map Location
Locus Symbol
Name
1
2
3
4
21pte~q21.1
21qll
21q11.2-q21.2
21q11.2-q21.2
21q21.1-qter
21q22.1-q22.2
21q22.1-qter
21q22.3
D21S26
D21S110
D21S1
D21S11
D21S24
D21S17
D21S113
D21S112
26C
21dU
pPW228C
pG95-al-lla
p21.3
pGSH8
pMCT15
CRI-L427'
U
U
U
U
E
E
-
E
€
E
-
u
U
U
U
-
5
-
E
E
-
-
-
-
E
E
E
E
-
-
-
€
8
7
8
9
€
€
€
E
-
E
-
-
€
-
E
'
-
-
E
E
-
€
E
-
E
11
12
-
€
-
-
E
E
-
€
€
€
-
10
E
€
E
E
-
E
€
13
E
E
E
E
-
-
-
E
E
-
-
E
E
-
E
E
E
-
E
Abbreviations: U, unequal; E, equal; -, unknown because only one band was observed or not tested.
VNTR probe.
2
a
(W
4.4
2a
2.0
6
b
a
5
------13 - -3 -7 8 --1
b
a
14
b
a
b
a
b
15
a
12
11
b
a
b
a
4
b
a
a
a
a
a
9 1 0
a
a
-
-
\
\
Fig 1. Reatrktlon fragment length polymorphh analysis of chromosome 2 In I w k m k wlls (lanes a) and nonlwkemk wlh (lanes b). lanes
am labeled with the petlent number. DNA was digested with Mspl and hvbrldlzedwith probe pYNH24, which recognizes a VMR polymorphism
on chromosome 2. The faint bands In the lanes containing DNA from leukemic cells of patients 2 and 8 represent residual normal bone marrow
cells present in the samples.
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ONODERA, McCABE, AND RUBIN
206
(kb)
3.0
-
2.0
-
5
1
2
4
1
2
4
10 11 12 13 C l
9
A
(kb)
6.1
-
4.1
-
5 9 1 0 11 12 13 c 2
c3
B
(kb)
C
18.5
12.3
-
1
3
6
7
0
IrUyI-1,-
a partial deletion of the short arm of chromosome 12 and a
dicentric chromosome 21, and two patients (patients & dnd
13) had marker chromosomes.
Analysis of wstrictionji-ament length polymorphism. We
first examined chromosomes present in two copies for loss
of heterozygosity. Two patients (patients 2 and 6) had
widespread loss of heterozygosity on all informative disomic chromosomes, and represent cases of near-haploid
ALL in which the chromosomes doubled." Eight probes
from eight chromosomes demonstrated loss of heterozygosity in patient 2 and eight probes from five chromosomes
Flg 2. Rsmiction fragment
lengthpolymorphismanalysbusing probes from chromosome 21.
Lanes containing DNA from leukemic samples are labeled with
the patient number. Lanes C1,
CZ, and C3 contain DNA from the
blood of healthy controls. (A)
DNA was digested with EcoM
and hybridizedwith probe pG95a l - l l a . (B) DNA was digested
with -1
and hybridized with a
VNTR probe CRI-l.427. (C) DNA
was digested with B@ll and hybridized with probe pGSHB. Results of densitometry of them
autoradiograms are shown in Table 4.
demonstrated loss of heterozygosity in patient 6. One
patient (patient 15) had loss of heterozygosity limited to
chromosome 3; this was demonstrated separately with
probes for the short and long arms of chromosome 3. Eight
loci on seven other disomic chromosomes in patient 15
retained heterozygosity. Loss of heterozygosity was not
detected in the remaining 12 patients; a total of 106
informative loci on 87 disomic chromosomes retained both
parental alleles (Fig 1 and Table 2).
We then examined the parental dosage of chromosome
21, when it was present in four copies. Eight probes for
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FORMATION OF A HYPERDIPLOID KARYOTYPE
chromosome 21 were used; informative results were obtained with three or more probes in all cases. Of the 13
patients without widespread loss of heterozygosity, 11
patients had tetrasomy 21; 10 of 11 (91%) had an equal
dose of maternal and paternal alleles on chromosome 21
and 1 of 11 (9%) had an unequal dose in a 3:l ratio. In all
patients the relative parental contribution was consistent at
several positions on chromosome 21 (Fig 2 and Table 3).
Results of densitometry for the three autoradiograms in
Fig 2 are shown in Table 4. Patient 1 had an approximately
3:l ratio in the density of the two allelic bands in autoradiograms made with three probes from chromosome 21. Two
other patients (patients 3 and 5) and normal controls had
an approximately equal ratio in the same experiments.
DISCUSSION
The results of this study provide molecular data pertinent
to the mechanism of formation of a hyperdiploid karyotype
with 250 chromosomes in childhood ALL. We have
considered four possible routes by which a normal diploid
precursor cell might become hyperdiploid: (1) development
of near-haploidy followed by doubling of the chromosomes;
(2) development of tetraploidy with subsequent loss of
chromosomes; (3) gains of individual chromosomes in a
sequential fashion through multiple independent nondisjunction events; and (4) simultaneous gain of multiple
chromosomes in a single abnormal cell division.
We have demonstrated the occasional occurrence of
route 1 in patients 2 and 6.l' There is widespread loss of
heterozygosity on all disomic chromosomes. A strong suspicion of this mechanism is raised by the karyotype in these
cases. Specifically, all chromosomes are present in either
two or four copies in the hyperdiploid clone. These cases
probably are classified best with near-haploid cases, which
have a relatively unfavorable prognosis.
The evidence produced by our study does not favor route
2. If a diploid cell were to become tetraploid and subsequently lose chromosomes, 33% of disomic chromosomes in
the hyperdiploid cell should have loss of heterozygosity.
This statement assumes that the chromosomes are lost
independent of the parental origin. In fact, we observed loss
of heterozygosity in only 1 of 95 (1%) of disomic chromosomes in patients with the typical form of the hyperdiploidy.
It is possible that selection against loss of heterozygosity led
in part to these results. Nevertheless, our best interpretation of the data is inconsistent with development of tetraploidy followed by loss of chromosomes.
Route 3 also is not supported by our results. With
independent gains of chromosomes by multiple nondisjunction events, it is predicted that 33% of instances of
tetrasomy would be characterized by a 2:2 parental dosage
and 67% by a 3:l dosage. Our findings, which were derived
from 11 patients with tetrasomy 21, were that 10 of 11
(91%) of the tetrasomies consisted of two maternal and two
207
Table 4. Densitometryof Polymorphic Bands Produced by Three
Probes From Chromosome 21
Ratio of Intensity (upper band:lower band)
Fig 2A
Patient 1
Patient 3
Patient 5
Control 1
Cohtrol2
Control 3
2.86:l.OO
Fig 2B*
Fig 2C
1.00:3.56
-
-
1.00:2.52
1.18:I.OO
1 .oo: 1.45
1.33:l.OO
1.07:l.OO
-
-
1.12:1.00
1 .oo: 1.02
-
-
-
-
*VNTR probe was used; mathematical correction was made according to the relative band size (see Materials and Methods and reference
14).
paternal copies of chromosome 21 and 1 of 11 (9%)
consisted of an unbalanced 3:l parental dosage. These data
suggest that the double gain of chromosome 21 occurs in a
single cell division as the result of a double nondisjunction;
this would consistently result in a 2:2 dosage. We suggest
that the chromosomal gains observed in typical cases of
hyperdiploid ALL occur in one step during one aberrant
cell division (route 4). Supportive of this idea are the
cytogenetict6 and DNA content studies17of cases of hyperdiploid ALL, which show distinct populations of normal
and hyperdiploid cells, but do not show a gradation of
intermediate cells.
It is difficult to propose a pathophysiologic basis for a
sudden gain of chromosomes in a cell. It is possible that it is
a reflection of the primary carcinogenic insult to the cell,
whether that be an unprovoked error of the mitotic apparatus or an imposed perturbance by an exogenous agent. In
either case the insult does not appear to be sustained,
because the abnormal karyotype, once formed, is uniform
and stable in the malignant cell population,
It remains unclear whether the hyperdiploid karyotype
itself contributes directly to the malignant process. Our
data do not support the possibility presented in the introduction that all of the extra chromosomes contain mutations
that give the cells a proliferative advantage. If this were the
case, the tetrasomic chromosomes should have a 3:l parental dosage. Also, we failed to identify a consistent defective
chromosomal region through an extensive search for loss of
heterozygosity. In two patients we found widespread loss of
heterozygosity and in one patient we found loss of heterozygosity limited to chromosome 3; whether loss of tumor
suppressor gene function played a role in these cases is
unknown. Additional studies of the molecular basis for this
leukemia subtype are needed.
ACKNOWLEDGMENT
We thank Drs Michelle M. Le Beau, Janet D. Rowley, Manuel
0. Diaz, and Robert Burnett for helpful discussions; Dr Stefan
Bohlander for assistance with the densitometry; and Drs Ellen
Solomon, Gordon D. Stewart, Bradley N. White, and Integrated
Genetics (Framingham, MA) for gifts of probes.
REFERENCES
1. Kaneko Y, Rowley JD, Variakojis D, Chilcote RR, Check I,
2. Heerema NA, Palmer GG, Baehner R L Karyotypic and
Sakurai M: Correlation of karyotype with clinical features in acute
clinical findings in a consecutive series of children with acute
lymphoblastic leukemia. Cancer Res 422918,1982
lymphoblastic leukemia. Cancer Genet Cytogenet 17:165, 1985
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
208
3. Prigogina EL, Puchkova GP, Mayakova S A Nonrandom
chromosomal abnormalities in acute lymphoblastic leukemia of
childhood. Cancer Genet Cytogenet 32:183,1988
4. Pui CH, Williams DL, Robertson PK, Raimondi SC, Behm
FG, Lewis SH, Rivera GK, Kalwinski DK, Abromowitch M, Crist
WM, Murphy SB: Correlation of karyotype and immunophenotype
in childhood acute lymphoblasticleukemia. J Clin Oncol6:56,1988
5. Fletcher JA, Kimball VM, Lynch E, Donnelly M, Pavelka K,
Galber RD, Tantravahi R, Sallan SE: Prognostic implications of
cytogenetic studies in an intensively treated group of children with
acute lymphoblastic leukemia. Blood 74:2130,1989
6. Uckun FM, Gajl-Peczalska KJ, Heerema N A Immunophenotype-karyotype associations in human acute lymphoblastic leukemia. Blood 73:271,1989
7. Pui CH, Raimondi SC, Dodge RK, Rivera GK, Fuchs LAH,
Abromowitch M, Look AT, Furman WL, Crist WM, Williams D L
Prognostic importance of structural chromosomal abnormalities in
children with hyperdiploid ( > 50 chromosomes) acute lymphoblastic leukemia. Blood 73:1963,1989
8. Williams DL, Look AT, Harber J, Murphy SB, Kalwinski DK,
Rivera GK, Melvin SL, Stass S, Dahl GV: Chromosomal translocations play a unique role in influencing prognosis in childhood acute
lymphoblastic leukemia. Blood 68:205,1986
9. The Third International Workshop on Chromosomes in
Leukemia. Cancer Genet Cytogenet 4:95,1981
10. Bloomfield CD, Secker-Walker LM, Goldman AI, Van Den
Berghe H, de la Chapelle A, Rutu T, Alimana G, Garson OM,
Golomb HM, Rowley JD, Kaneko Y, Whang-Peng J, Prigogina E,
Philip P, Sandberg AA, Lawler SD, Mitelman F: Six-year follow-up
of the clinical significance of karyotype in acute lymphoblastic
leukemia. Cancer Genet Cytogenet 40171,1989
ONODERA, McCABE, AND RUBIN
11. Onodera N, McCabe NR, Nachman JB, Johnson FL, Le
Beau MM, Rowley JD, Rubin CM: Hyperdiploidy arising from
near-haploidy in childhood acute lymphoblastic leukemia. Genes
Chromosomes Cancer (in press)
12. Tsuchiya H, Matsuda I, Kaneko Y: Why does childhood
acute lymphoblastic leukemia with hyperdiploidy show a favorable
prognosis? Cancer Genet Cytogenet 50273,1991 (letter)
13. Harnden DG, Klinger HP (eds): ISCN, An International
System for Human Cytogenetic Nomenclature; published in collaboration with Cytogenet Cell Genet, Karger, Basel, 1985; also in
Birth Defects: Original Article Series, Vol 21, No 1, March of
Dimes Birth Defects Foundation, New York, NY, 1985
14. Yamada T, Shippey CA, Martineau M, Secker-Walker LM:
Demonstration of acquired hemizygosity and clonality in acute
lymphoblastic leukemia with chromosome 7 abnormalities using
hypervariable DNA probes. Genes Chromosomes Cancer 2:88,
1990
15. Kidd ICK, Bowcock AM, Schmidtke J, Track RK, Riccinti F,
Hutching G, Bale A, Pearson P, Willard H F Tenth International
Workshop on Human Gene Mapping: Report of the DNA committee and catalogs of cloned and mapped genes and DNA polymorphisms. Cytogenet Cell Genet 51:622,1989
16. Williams DL, Tsiatis A, Brodeur GM, Look TA, Melvin SL,
Bowman WP, Kalvinsky DK, Rivera G, Dahl G Prognostic
importance of chromosome number in 136 untreated children with
acute lymphoblasticleukemia. Blood 60:864, 1982
17. Look AT, Robertson PK, Williams DL, Rivera GK, Bowman
WP, Pui CH, Ochs J, Abromowitch M, Kalwinsky D, Dahl GV,
George S, Murphy S B Prognostic importance of blast cell DNA
content in childhood acute lymphoblasticleukemia. Blood 65:1079,
1985
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1992 80: 203-208
Formation of a hyperdiploid karyotype in childhood acute
lymphoblastic leukemia [see comments]
N Onodera, NR McCabe and CM Rubin
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