Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Abstract

Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPN11 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 PTPN11 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 PTPN11 mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPN11 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 PTPN11 mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs. V V C 2007 Wiley-Liss, Inc.

Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

“…Rather, the increased catalytic activity (8,9) and enhanced binding of GOF mutant Shp2 to its interacting proteins (14-16) directly disturb mitosis and cytokinesis, evoking chromosomal instability and other genetic alterations that cooperatively drive tumor cell formation. The notion that Shp2 GOF mutations induce chromosomal instability is also supported by clinical observations, in which Ptpn11 GOF mutations were frequently found in childhood leukemias with hyperdiploid DNA content (11,33), karyotypic changes were often observed in JMML patients with Ptpn11 mutations (34,35), and Noonan syndrome patients with Ptpn11 mutations were predisposed to hematological malignancies, relative to Ptpn11 mutation-negative cases (36).…”

High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event

“…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.…”

Targeted next-generation sequencing detects point mutations, insertions, deletions and balanced chromosomal rearrangements as well as identifies novel leukemia-specific fusion genes in a single procedure

“…19 The analysis of KRAS mutations in codons 12, 13 and 61 was carried out as previously described. 20 Exons 2 and 3 were amplified by PCR, and PCR products were analyzed using the BigDye terminator v1.1 cycle sequencing kit (Applied Biosystems, Darmstadt, Germany). Analyses for NPM1 mutations, FLT3 internal tandem duplications, FLT3 tyrosine kinase domain mutations, KITD816 mutations and KIT exon 8 mutations were performed as described previously.…”