“…Two groups of mutations were identified as putative driver events: those occurring in genes involved in the rat sarcoma (RAS) signaling pathway, including fms-related tyrosine kinase 3 (FLT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), in 50% of the cases, and those occurring in histone modifier genes, primarily CREB binding protein (CREBBP) and Wolf-Hirschhorn syndrome candidate 1 (WHSC1), in 20% of cases. Although mutations in these genes were known to occur in high hyperdiploid childhood ALL, 3,4 the frequency was higher than reported previously, partly due to a high number of KRAS mutations outside the hotspot regions in codons 12, 13, and 61. 2 Notably, in a very recent study of relapsed high hyperdiploid childhood ALL, Malinowska-Ozdowy et al 5 showed that KRAS and CREBBP mutations commonly co-occur at relapse, indicating that mutations in these genes have synergistic effects, in particular when the leukemic clones are subjected to selective pressures during chemotherapy.…”