Mutations of FLT3, NRAS, KRAS, and PTPNII are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPNII genes are particularly frequent in high hyperdiploid (> 50 chromosomes) pediatric acute lymphoblastic leukemias (ALLs), this has as yet not been confirmed in a large patient cohort. Furthermore, it is unknown whether mutations of these genes coexist in hyperdiploid cases. We performed mutation analyses of FLT3, NRAS, KRAS, and PTPNII in a consecutive series of 78 high hyperdiploid ALLs. Twenty-six (33%) of the cases harbored a mutation, comprising six activating point mutations and one internal tandem duplication of FLT3 (7/78 cases; 9.0%), eight codon 12, 13, or 61 NRAS mutations (8/78 cases; 10%), five codon 12 or 13 KRAS mutations (5/78 cases, 6.4%), and seven exon 3 or 13 PTPNII mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPNII and gender, age, white blood cell count, or relapse, suggesting that they do not confer a negative prognostic impact. Only one case harbored mutations in two different genes, suggesting that mutations of these four genes are generally mutually exclusive. In total, one third of the cases harbored a FLT3, NRAS, KRAS, or PTPNII mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs. (c) 2007 Wiley-Liss, Inc.