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Association of Germline p53 Mutation With MLL Segmental Jumping
Translocation in Treatment-Related Leukemia
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.
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.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4451-4456
© 1998 by The American Society of Hematology.
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