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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4451-4456
Association of Germline p53 Mutation With MLL Segmental Jumping
Translocation in Treatment-Related Leukemia
By
Carolyn A. Felix,
Maureen D. Megonigal,
David S. Chervinsky,
Debra G.B. Leonard,
Nao Tsuchida,
Surabhi Kakati,
Anne Marie
W. Block,
John Fisher,
Mauro Grossi,
Kevin I. Salhany,
Sheila N. Jani-Sait, and
Peter D. Aplan
From the Division of Oncology, The Children's Hospital of
Philadelphia, Department of Pediatrics, Department of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine, and
Molecular Diagnostics Core Facility, University of Pennsylvania Cancer
Center, Philadelphia, PA; the Departments of Pediatrics and Molecular
Immunology, Clinical Cytogenetics Laboratory, Roswell Park Cancer
Institute, Buffalo, NY; and the Departments of Pathology
and Pediatrics, Children's Hospital of Buffalo, Buffalo, NY.
 |
ABSTRACT |
Segmental jumping translocations are chromosomal abnormalities in
treatment-related leukemias characterized by multiple copies of the
ABL and/or MLL oncogenes dispersed throughout
the genome and extrachromosomally. Because gene amplification potential
accompanies loss of wild-type p53, we examined the p53 gene in a case
of treatment-related acute myeloid leukemia (t-AML) with MLL
segmental jumping translocation. The child was diagnosed with
ganglioneuroma and embryonal rhabdomyosarcoma (ERMS) at 2 years of age.
Therapy for ERMS included alkylating agents, DNA topoisomerase I and
DNA topoisomerase II inhibitors, and local radiation. t-AML was
diagnosed at 4 years of age. The complex karyotype of the t-AML showed
structural and numerical abnormalities. Fluorescence in situ
hybridization analysis showed multiple copies of the MLL gene,
consistent with segmental jumping translocation. A genomic region
including CD3 , MLL, and a segment of band 11q24 was
unrearranged and amplified by Southern blot analysis. There was no
family history of a cancer predisposing syndrome, but single-strand
conformation polymorphism (SSCP) analysis detected
identical band shifts in the leukemia, ganglioneuroma, ERMS, and normal
tissues, consistent with a germline p53 mutation, and there was loss of
heterozygosity in the ERMS and the t-AML. Sequencing showed a
CGA TGA nonsense mutation at codon 306 in exon 8. The results
of this analysis indicate that loss of wild-type p53 may be associated
with genomic instability after DNA-damaging chemotherapy and radiation,
manifest as a complex karyotype and gene amplification in some cases of
t-AML.
| |
INTRODUCTION |
USING FLUORESCENCE in situ hybridization
(FISH) analysis, Tanaka et al1 recently identified jumping
translocations of the chromosomal segments containing the ABL
or MLL oncogenes as a new form of gene amplification in three
treatment-related leukemias with complex karyotypes. The leukemias were
of French-American-British (FAB) M1, M2, or M4 morphologic subtypes and
followed various classes of DNA-damaging chemotherapy and radiation
used for the management of adult solid tumors.1 The
karyotypes contained chromosome 5 or 7 monosomy typical of alkylating
agent-induced leukemias, as well as several other numerical and
structural abnormalities.1 The segmental jumping
translocations were characterized by multiple copies of the ABL
or MLL oncogenes dispersed throughout the genome and
extrachromosomally.1
The complex karyotypes and ABL and MLL gene
amplification in treatment-related leukemias with segmental jumping
translocations suggest genomic instability. The G1 cell cycle
checkpoint function of wild-type p53 maintains genomic stability and
ploidy. With DNA-damaging chemotherapy and  -radiation, the altered
cell cycle arrest associated with loss of wild-type p53 is associated
with genomic instability.2-5
In the present study, we identified MLL gene amplification
consistent with segmental jumping translocation in a pediatric case of
treatment-related acute myeloid leukemia (t-AML) with a complex
karyotype. The child previously received multiagent chemotherapy and
local radiation for nasopharyngeal embryonal rhabdomyosarcoma (ERMS)
diagnosed at 2 years of age. We examined the p53 gene for mutation
because germline p53 mutations are associated with early onset
ERMS6 and because loss of wild-type p53 is associated with
gene amplification in in vitro model systems.2 The
mechanism for gene amplification in leukemias with segmental jumping
translocations previously was unknown. Detection of a germline p53
mutation with loss of heterozygosity (LOH) in this t-AML indicates that
one mechanism is loss of wild-type p53.
| |
MATERIALS AND METHODS |
The Institutional Review Boards at the Children's Hospital of Buffalo
and the Children's Hospital of Philadelphia approved this research and
the parents gave informed consent. Karyotype, FISH, and Southern blot
analyses were performed on the t-AML of patient RUPN 84 and on the cell
line 2L1, which was derived from the marrow of patient RUPN 84 at
diagnosis of t-AML.
Characterization of the cell line 2L1.
The cell line 2L1 was continuously passaged for 14 months in Iscove's
modified Minimum Essential Medium (MEM; Life Technologies, Inc,
Gaithersburg, MD) containing 20% fetal bovine serum, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin.
The diagnostic marrow and the 2L1 cells expressed CD33, CD13, CD15, CD11b, and CD38; however, the 2L1 cells were also strongly positive (>90%) for CD2, CD10, and CD56. The karyotypes of the 2L1 cells and
of the diagnostic marrow of patient RUPN 84 were the same (see
Results).
Cytogenetic analysis.
Bone marrow of patient RUPN 84 at diagnosis of t-AML was cultured for
24 hours with and without methotrexate synchronization and processed by
conventional cytogenetic methods.7 Methaphase chromosomes
were trypsin/Wright stain banded, and karyotypes were described
according to ISCN guidelines.8
FISH analysis.
Probes used for FISH analysis included a YAC clone containing MLL
(Oncor, Gaithersburg, MD), a CD3 probe for analysis
of the region centromeric to the MLL gene (a kind gift from Dr
Thomas Shows, Roswell Park Cancer Institute, Buffalo, NY), and the more telomeric cosmid, C11q7q24, from chromosome band 11q24.9
The probes were labeled with digoxigenin, and metaphase spreads from the marrow of patient RUPN 84 at diagnosis of t-AML and from the cell
line 2L1 were examined by FISH analysis using standard
methods.10
Southern blot analysis of the MLL gene.
Genomic DNAs from the diagnostic marrow of patient RUPN 84, from the
cell line 2L1, and from control peripheral blood mononuclear cells were
examined by Southern blot analysis. BamHI-, HindIII-, Sst I-, EcoRI-, and Bgl II-digested DNAs were
hybridized with a 0.7-kb cDNA probe from the MLL
bcr.11 BamHI- and HindIII-digested DNAs
were also hybridized with a 2.2-kb genomic fragment of the SCL
gene at chromosome band 1p33-1p34.12 To assess equivalence in loading, HindIII-digested DNAs were simultaneously
hybridized with the MLL bcr cDNA probe11 and the
SCL genomic probe.12
BamHI-, HindIII-, and EcoRI-digested DNAs were
hybridized with polymerase chain reaction (PCR)-generated fragments
from MLL exon 3, exon 25, and exon 34. The sense and antisense
PCR primers used to amplify MLL exon 3 were 5 -GTC AGT
GCT ATC TCC TCG CG-3 and 5-GCA GAA GTT CGA TTA CTA
GGC-3, respectively. The sense and antisense PCR primers used to
amplify MLL exon 25 were 5-CTT ACC ACA GGA CTA AAT
CC-3 and 5-TTA TGA TGT TGG GGA CAG TTC G-3, respectively. The sense and antisense PCR primers used to amplify MLL exon 34 were 5-CAG AGA CAG AGT TGA GGT CTC
G-3 and 5-CAG AAG TGA ACT CTC GAG TGG-3,
respectively. BamHI-, HindIII-, and Sst
I-digested DNAs were hybridized with a 1.3-kb cDNA probe from the
CD3 gene, which is centromeric to the MLL gene at chromosome band 11q23 (a kind gift from Dr Thomas Shows). Southern blot analysis also was performed on BamHI- and HindIII-digested DNAs
using a 1.5-kb nonreiterated genomic fragment, C11q1.5SS, from the
cosmid C11q7q24, which maps to chromosome band 11q24.9
Signal intensity on the autoradiographs was quantitated using a
Molecular Dynamics computing densitometer and ImageQuant software (Molecular Dynamics, Sunnyvale, CA). The MLL, CD3, and band
q24 chromosome 11 signals were normalized by comparison with the signal from hybridization with the SCL probe from chromosome band
1p33-1p34.
p53 single-strand conformation polymorphism (SSCP)
analysis.
Genomic DNAs from the marrow of patient RUPN 84 at diagnosis of t-AML
and from the cell line 2L1 were screened by PCR/SSCP analysis.13 The oligonucleotide primers have been
reported.14 PCR fragments containing p53 exons 5 and 6 or
exons 7 and 8 and incorporating [ 32P]-dCTP were
amplified using 100 ng genomic DNA as template. Aliquots of the
products containing exons 5 and 6 or exons 7 and 8 were digested with
Aat I or Dra I, respectively, to reduce the fragment sizes and separate the exons. Aliquots of the digested products were
diluted with loading buffer, denatured by heating at 90°C for 5 minutes and electrophoresed at 4°C in nondenaturing polyacrylamide at constant power as previously described.13
Characterization of p53 mutation suggested by SSCP.
Fresh aliquots of genomic DNA from the marrow of patient RUPN 84 at
diagnosis of t-AML were amplified in 3 separate PCR reactions with the
same SSCP primers encompassing exons 7 and 8. The 100 µL PCR reaction
mixtures contained 1 µg genomic DNA, 2.5 U AmpliTaq DNA
polymerase, 200 mmol/L of each dNTP, PCR reaction buffer at 1×
final concentration (Perkin Elmer, Norwalk, CT), and 100 pmol of each
primer. After initial denaturation at 94°C for 9 minutes, 35 cycles
at 94°C for 1 minute, 55°C for 1 minute, and 72°C for 2 minutes were used, followed by a final elongation at 72°C for 7 minutes. Products of 3 separate PCR reactions were subcloned into
pBluescript II SK+ vector (Stratagene, La Jolla,
CA). Six separate subclones from the 3 independent PCR
reactions were sequenced by automated methods.
Extraction of genomic DNAs from paraffin-embedded tissues for SSCP
analysis of p53 exon 8.
Genomic DNAs were extracted from formalin-fixed paraffin-embedded
tissue blocks of the ERMS and ganglioneuroma of patient RUPN 84. After
thorough cleaning of the microtome and installation of a new disposable
knife, 15- to 20-µm sections providing a 1 cm2 area were cut from a control blank block and from the
blocks containing tissue. Microdissection was performed to isolate the tumor from the surrounding normal tissue. The sections were
deparaffinized with a 1:1 mixture of xylene and ethanol. Deparaffinized
sections were incubated at 55°C for 1 to 3 hours in 100 µL of a
solution containing 6 µg proteinase K, 10 mmol/L Tris HCl, pH 8.3, 50 mmol/L KCl, 1.5 mmol/L MgCl2, and 0.01% gelatin. The
solutions then were incubated at 100°C for 10 minutes, followed by
microcentrifugation at 14,000 rpm for 10 minutes. The supernatant
containing the DNA was removed to a clean microcentrifuge tube and
diluted with dH2O to a final volume of 200 µL.
SSCP analysis of p53 exon 8 in genomic DNAs from paraffin-embedded
tissues.
A new PCR/SSCP sense primer beginning at the Dra I site in p53
intron 7 was designed to amplify a 245-bp product containing p53 exon 8 when used with the same intron 8 antisense primer as described
above.14 The sense primer was homologous to positions 13937-13954 of the p53 genomic sequence. One hundred nanograms of
genomic DNA from the marrow of patient RUPN 84 at diagnosis of t-AML
and 2 µL of genomic DNAs prepared from the paraffin-embedded tissues
were amplified in 10 µL reactions incorporating
[32P]-dCTP using exactly the same PCR conditions as
described above for SSCP.13 Blank blocks processed in the
same manner as the paraffin-embedded tissues and dH2O were
negative controls. One microliter of each PCR reaction was diluted with
9 µL of loading buffer and denatured by heating at 90°C for 5 minutes. Two microliters of each heat-denatured sample (1/50 of the
initial PCR reaction) was electrophoresed at 4°C in nondenaturing
polyacrylamide at constant power for 5 hours.
| |
RESULTS |
Case history.
Patient RUPN 84 was diagnosed simultaneously with ganglioneuroma and
nonmetastatic nasopharyngeal ERMS at 2 years of age. Treatment for ERMS
included multiagent chemotherapy and local radiation. Cumulative
chemotherapy doses for ERMS were vincristine (40 mg/m2),
actinomycin D (17.5 mg/m2), ifosfamide (7,300 mg/m2), and cyclophosphamide (8,600 mg/m2).
Additional therapy doses for locally recurrent ERMS were etoposide (1,200 mg/m2), doxorubicin (300 mg/m2), and
carboplatinum (3,810 mg/m2). The child was diagnosed with
t-AML at 4 years of age after 10 months off therapy for ERMS. There was
no family history of a cancer-predisposing syndrome. The diagnostic
marrow contained 60% blasts of the FAB M5 monoblastic subtype that
expressed CD33, CD13, CD15, CD11b, and CD38. The complex karyotype of
the t-AML was 45,XY,
der(5)t(5;11)(5pter5q12::11q2311qter),der(11)(pterq12::q24q12::q13qter),  17. Remission induction with daunomycin, cytosine arabinoside, thioguanine, and teniposide was unsuccessful. The patient underwent HLA-matched allogeneic marrow transplantation but died from his disease.
Evidence for MLL gene amplification in the t-AML of patient RUPN 84.
Consistent with segmental jumping translocation, 5 or 6 signals
consistently were identified on hybridization of the MLL YAC probe with a total of 20 metaphase spreads prepared from the diagnostic marrow of patient RUPN 84. In the example shown in
Fig 1, the MLL YAC probe detected
signals on the der(5) chromosome, on the normal chromosome 11, and at
distinct centromeric and telomeric regions on the der(11) chromosome.
The telomeric and centromeric signals from the der(11) chromosome were
consistently more intense than the MLL signal from the normal
chromosome 11, suggesting that the centromeric and telomeric regions on
the der(11) chromosome contained multiple copies of the MLL
gene. In addition, at least 5 discrete signals were observed in the
nearby interphase nucleus (Fig 1). Similar results were obtained by
FISH analysis with CD3 and 11q24 probes, indicating that the
amplified genomic region extended centromeric and telomeric of the
MLL gene. FISH analysis of the cell line 2L1 derived from the
leukemia showed the same results (data not shown).
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| Fig 1.
FISH analysis demonstrating multiple copies of
MLL in t-AML of patient RUPN 84. Digoxygenin-labeled
MLL YAC probe (Oncor) was hybridized to metaphase spread.
Centromeric and telomeric signals are detected on der(11) chromosome (9 o'clock). Signals also are detected on der(5) chromosome (6 o'clock)
and on normal chromosome 11 (3 o'clock). There are 5 discrete signals
on nearby interphase nucleus. Five or 6 signals consistently were
detected on hybridization of MLL YAC probe with other metaphase
spreads from the t-AML.
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|
Consistent with the FISH analysis, Southern blot analysis suggested
that there were multiple copies of the MLL gene in the t-AML of
patient RUPN 84 and in the cell line 2L1
(Fig 2). The ratio of MLL signal
intensities in the t-AML and in the cell line 2L1 were 4.3:1 compared
with the peripheral blood mononuclear cell (PBMC) control
when normalized for equal loading by hybridization with the SCL
probe. These results suggest approximately 8 to 9 copies of the
MLL gene in the t-AML of patient RUPN 84 and in the cell line
2L1 derived from the leukemia (Fig 2). Although the patient received
DNA topoisomerase II-targeted chemotherapy and had monoblastic
leukemia, the MLL gene was not rearranged by Southern blot
analysis. The results of Southern blot analysis with multiple
restriction digests used in combination with MLL exon 3, exon
25, and exon 34 probes and a CD3 probe showed similar unrearranged,
amplified patterns, whereas hybridization with an 11q24 probe showed
the unrearranged pattern but less amplification (2.0:1), again
indicating that the amplified region extended both centromeric and
telomeric of the MLL gene (data not shown).
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| Fig 2.
Southern blot analysis demonstrating multiple copies of
the MLL gene in t-AML of patient RUPN 84 and cell line 2L1.
BamHI- and HindIII-digested DNAs were hybridized
separately with MLL bcr cDNA and SCL genomic probes
(A). Although the patient received DNA topoisomerase II-targeted
chemotherapy and had monoblastic leukemia, the MLL gene was not
rearranged. HindIII-digested DNAs were hybridized
simultaneously with MLL bcr cDNA and SCL genomic probes
to assess equivalence in loading (B). The bold arrow in (B) indicates
MLL signals; the thin arrow indicates SCL signals. The
increased MLL signal intensity compared with PBMC control, 4.3:1 when normalized for loading by hybridization with SCL
probe, is consistent with approximately 8 to 9 copies of the
MLL gene in the t-AML and cell line 2L1.
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Association of MLL gene amplification with p53 mutation.
SSCP analysis of genomic DNAs from the marrow of patient RUPN 84 at
diagnosis of t-AML and from the cell line 2L1 detected identical band
shift patterns and LOH in the region of p53 exon 8 (Fig 3). Sequencing of 6 individual genomic
subclones from 3 independent PCR reactions performed on the marrow DNA
identified a CGATGA nonsense mutation at codon 306 that
created a premature termination codon and would foreshorten the
predicted protein. SSCP analysis of p53 exon 8 in DNA prepared from
paraffin-embedded tissues showed the same band shift pattern in the
normal tissues and in the sarcoma and ganglioneuroma, indicating that
the p53 mutation was of germline origin. There was LOH in the sarcoma but not in the ganglioneuroma. As predicted with a truncated protein, p53 immunostaining was negative in the ganglioneuroma and in the sarcoma (data not shown).
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| Fig 3.
Detection of germline p53 mutation in patient RUPN 84. SSCP analysis of genomic DNA from the t-AML and from cell line 2L1 showed identical band shift patterns with LOH in the region of p53 exon
8 (arrow, left). Schematic of strategy for PCR amplification and
Dra I restriction enzyme cleavage and resultant sizes of
genomic DNA fragments containing p53 exon 7 and p53 exon 8 are shown
below. SSCP analysis of p53 exon 8 in t-AML DNA and DNAs prepared from paraffin-embedded tissues showed the same band shift pattern in the
ganglioneuroma, ERMS, and surrounding normal tissues, indicating that
the p53 mutation was of germline origin (right). T, tumor tissue; N,
normal tissue. There was LOH in the t-AML and the ERMS, but not in the
ganglioneuroma. Sequencing of individual genomic subclones from t-AML
DNA detected a CGATGA nonsense mutation at p53 codon 306 that
created a premature termination codon and would foreshorten the
predicted protein.
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| |
DISCUSSION |
We used FISH and Southern blot analysis to determine MLL gene
copy number in a t-AML with a complex karyotype and monoblastic features and detected MLL gene amplification consistent with
the jumping translocations of chromosomal segments containing
MLL or ABL that were first discovered by Tanaka et
al1 in 1997. Detailed molecular analyses demonstrated that
the amplified MLL gene was not rearranged. The prior history of
early onset ERMS and DNA damaging chemotherapy and radiation, and the
central role of wild type p53 in maintaining genomic stability and
ploidy,15 led to the investigation of the p53 gene and
detection of the germline codon 306 mutation and LOH in the ERMS and
the t-AML.
This case brings the total number of treatment-related leukemias with
segmental jumping translocations that have been described to
four. With additional detailed FISH and molecular
analyses, the incidence of segmental jumping translocations in
treatment-related leukemias should become apparent, because the
abnormalities are not detected by karyotype alone. Consistent with the
FISH analyses of Tanaka et al,1 we determined that there
was intrachromosomal amplification of the specific segment containing
MLL and that the segment containing MLL had moved to at
least one other chromosome. Although the t-AML was monoblastic,
Southern blot analysis showed that the amplified MLL gene,
including regions 5 and 3 of the breakpoint cluster
region, was not rearranged. The results of FISH and Southern blot
analyses with CD3 and 11q24 probes indicate that the amplified,
unrearranged genomic region extended centromeric and telomeric of the
MLL gene. Disruption of the breakpoint cluster region of the
MLL gene by chromosomal translocation specifically is
associated with the development of leukemia,16 but the role of MLL gene amplification in leukemogenesis currently is
unknown.
The karyotype of the t-AML that we examined and the karyotypes of the
other three leukemias with segmental jumping translocations were
complex1 and suggest genomic instability. In this regard, the t-AML was similar to an alkylating agent-induced leukemia in which
we previously detected a germline 2-bp deletion at p53 codon 209 that
was inherited from the father.17 In the latter case, FISH
analysis was not performed and it is not known whether there was a
segmental jumping translocation, but the karyotype was 45, XY,
hsr(2)(q22), 5, der(7)del(7)(q11.23)hsr(7)(q11.23), der(12)t(12;19)(p11.2;q12),
der(17)t(5;17)(p12;p11.2),19,+mar1.17
As was true for the child in the present study, the patient was
diagnosed at an early age (1 year and 10 months) with primary ERMS, and
there was not a family history of the Li-Fraumeni
syndrome.17 In a study of patients with RMS without family
histories of the Li-Fraumeni syndrome, Diller et al6
detected germline p53 mutations in 3 of 13 children diagnosed before 3 years of age, but found no germline p53 mutations in 20 older children.
These observations suggest that germline p53 mutations may predispose a
fraction of young children undergoing therapy for RMS to t-AML, because the defective G1 cell cycle checkpoint that accompanies loss of wild-type p53 brings about genomic instability with DNA damaging chemotherapy and radiation.15
Wild-type p53 blocks cell cycle progression in late G1 in the presence
of DNA damage caused by certain anticancer drugs and radiation and,
depending on the level of the damage, either mediates apoptosis or
permits DNA repair and cell cycle re-entry.3-5,18-23 p53-dependent apoptosis is responsible, in part, for the cytotoxic activity of anticancer drugs and -radiation, while cells deficient in wild-type p53 are resistant to the induction of apoptosis by these
agents.22-24
p53 mutant cells lose the ability to inhibit cell growth after
DNA-damaging chemotherapy and -radiation.4,5 Thus, p53 was a candidate gene to examine in a t-AML with gene amplification because wild-type p53 maintains genomic stability and ploidy, whereas
altered cell cycle arrest, gene amplification potential and aneuploidy
occur with loss of wild-type p53.2,3 Furthermore, heterozygosity for mutant p53 does not result in gene amplification in
experimental systems.2,3 In the leukemia in this study, p53
SSCP analysis showed both mutation and LOH and the karyotype showed
chromosome 17 monosomy, which explains the LOH.
The child in the present study and 3 patients with t-AML with
ABL and MLL segmental jumping translocations reported
on by Tanaka et al1 received heterogeneous chemotherapy
and, in some cases, radiation. Our own observations suggest that young
children with RMS and germline p53 mutations may be at increased risk
for t-AML resulting from genomic instability on exposure to genotoxic agents.17 There is insufficient information to recommend
treatment changes based on the current knowledge, but systematic study
of p53 mutations and prior therapy in a larger cohort of patients with
this form of t-AML may inform the rational design of individualized primary cancer treatment for at-risk individuals.
The results of this analysis establish that the pathogenesis of the
gene amplification in treatment-related leukemias with segmental
jumping translocations involves loss of wild-type p53. Just as gene
amplification potential accompanies loss of wild-type p53 in
Li-Fraumeni fibroblasts in vitro,2 germline p53 mutations with LOH may be associated with MLL gene amplification in
t-AML. In vitro studies also indicate that there are alternative
pathways that allow gene amplification when p53 is
wild-type.2 The frequency of mutant p53 in
treatment-related leukemias with segmental jumping translocations
remains to be determined. Hartwell15 suggested that genomic
instability is a genetic trait. The demonstration of a germline p53
mutation in association with the complex karyotype and MLL gene
amplification in the t-AML in the present study proves that this is
indeed the case. Future studies will explore the roles of the specific
genetic changes resulting from the instability in the genesis of
leukemia.
| |
FOOTNOTES |
Submitted January 21, 1998;
accepted March 26, 1998.
C.A.F. is supported by American Cancer Society Grant No. DHP143,
National Institutes of Health Grant No. 1R29CA66140-03, a Leukemia
Society of America Scholar Award (1996-2001), the National Childhood
Cancer Foundation, a National Leukemia Research Association Grant in
Memory of Maria Bernabe Garcia, and The Children's Hospital of
Philadelphia High Risk High Impact Grant. P.D.A. is supported by
National Institutes of Health Grants No. CA73773 and CA15606 and the
Leukemia Society of America Scholar Award (1997-2002).
Address reprint requests to Carolyn A. Felix, MD, Division of Oncology,
Leonard and Madlyn Abramson Pediatric Research Center, Room 902B,
Children's Hospital of Philadelphia, 324 S 34th St, Philadelphia, PA
19104-4318.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract