RAS mutations in pediatric leukemias with MLL gene rearrangements

Abstract

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 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 mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation 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 leukemias with similar translocations.

Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein

“…45 MLL fusion proteins including the AF4 family and AF6 are also involved in Ras signaling, [46][47][48] and N-ras and K-ras mutation have been reported for leukemia patients with t(11; 17)(q23; q25) and other MLL translocations. 49,50 The pathologic significance of the Ras-mediated pathways in MLL leukemogenesis is further strengthened by the identification of EEN SH3 domain as a critical transformation domain, which is sufficient for MLL-EEN-mediated myeloid transformation (C.W.S. et al, unpublished observations, 2003).…”

Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein

“…HL60 cells express bcl-2 and bax, overexpress c-myc, but do not express p53, and N-ras is mutated (Mollinedo et al, 1998). Since additional events, including mutations in p53 and N-ras, and deregulated bcl-2 function, have been documented to accompany MLL rearrangements in some cases (Naoe et al, 1993;Pocock et al, 1995;Lanza et al, 1996;Mahgoub et al, 1998), it is reasonable to speculate that the oncogenic potential of MLL fusion protein will be potentiated in the cells with such mutations. We thus took advantage of HL60 cells to study the oncogenic properties of MLL-EEN.…”

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

“…For instance, Liang et al reported RAS mutations in 10 of 20 (50%) of the cases, while Mahgoub et al could not identify RAS mutations among 13 MLLrearranged ALL samples. 11,12 Besides, Tamai et al speculate that the short latency in their KRAS mutation-positive mouse model is likely due to an acceleration of leukemolymphomagenesis by a collaborative upregulation of HOXA9. 9 HOXA overexpression is often believed to be a hallmark of MLL-rearranged leukemia and has recently been proposed to be required for leukemia survival of MLLrearranged acute myeloid leukemia (AML) cells.…”