ASSOCIATION OF GERMLINE P53 MUTATION WITH MLL SEGMENTAL JUMPING TRANSLOCATION IN TREATMENT-RELATED LEUKEMIA

Segmental jumping translocations are chromosomal abnormalities in trea tment-related leukemias characterized by multiple copies of the ABL an d/or MLL oncogenes dispersed throughout the genome and extrachromosoma lly. Because gene amplification potential accompanies loss of wild-typ e p53, we examined the p53 gene in a case of treatment-related acute m yeloid 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 r adiation. t-AML was diagnosed at 4 years of age. The complex karyotype of the t-AML showed structural and numerical abnormalities. Fluoresce nce in situ hybridization analysis showed multiple copies of the MLL g ene, consistent with segmental jumping translocation. A genomic region including CD3 epsilon, MLL, and a segment of band 11q24 was unrearran ged and amplified by Southern blot analysis. There was no family histo ry of a cancer predisposing syndrome, but single-strand conformation p olymorphism (SSCP) analysis detected identical band shifts in the leuk emia, ganglioneuroma, ERMS, and normal tissues, consistent with a germ line p53 mutation, and there was loss of heterozygosity in the ERMS an d 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-damagin g chemotherapy and radiation, manifest as a complex karyotype and gene amplification in some cases of t-AML. (C) 1998 by The American Societ y of Hematology.