RAS MUTATIONS IN PEDIATRIC LEUKEMIAS WITH MLL GENE REARRANGEMENTS

Translocations of the MLL gene at chromosome band 11q23 are the most c ommon cytogenetic alterations in de novo leukemia in infants and in le ukemia related to chemotherapy with DNA topoisomerase II inhibitors. E xperiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-str and conformation polymorphism analysis and an allele-specific restrict ion enzyme assay to investigate the frequency of KRAS and NRAS mutatio ns in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia(ALL), 10 were acu te myeloid leukemia (AML), and 2 were biphenotypic. Three secondary le ukemias were AML, was biphenotypic, I was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS muta tions were otherwise absent in this series. This is the first report o f congenital leukemias where translocation of the MLL gene and RAS mut ation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leuke mias with similar translocations. (C) 1998 Wiley-Liss, Inc.