Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia.
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.
Felix
C A
CA
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
Megonigal
M D
MD
Chervinsky
D S
DS
Leonard
D G
DG
Tsuchida
N
N
Kakati
S
S
Block
A M
AM
Fisher
J
J
Grossi
M
M
Salhany
K I
KI
Jani-Sait
S N
SN
Aplan
P D
PD
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D004268:DNA-Binding Proteins / Q000235:genetics*; D018095:Germ-Line Mutation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes; D014157:Transcription Factors; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase