Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Abstract

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/ AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with À7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of À5/5q-and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, Po0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signalregulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/ RUNX1 mutations has a significant association with À7/7q-alteration, and frequently involves RTK-RAS signaling pathway activation.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

“…11,40 As shown in Table 4 and supplemental Table 3, 31 of the 62 RUNX1-mutated patients (50%) concurrently had other gene mutations and the majority (26 of 31, 83.9%) simultaneously showed class I mutations, most commonly FLT3/ITD, FLT3/TKD, and N-RAS, which might result in hyperactivation of the receptor tyrosine kinase-RAS signaling pathways. 41 This finding was consistent with the current hypothesis of 2-hit model of leukemogenesis. 5,6 However, MLL/PTD, another class II mutation, was also found in a significantly higher frequency in RUNX1-mutated patients (9 of 62, 14.5%) than in RUNX1-wild patients (19 of 408, 4.7%, P ϭ .006).…”

Genetic Alterations and Their Clinical Implications in Acute Myeloid Leukemia

“…(Dicker, et al 2007, Schnittger, et al 2011, Tang, et al 2009 (Tang, et al 2009) which all result in hyperactivation of the receptor tyrosine kinase (RTK)-RAS signalling pathways. (Niimi, et al 2006) This finding is consistent with the two-hit model of leukemogenesis. (Frohling, et al 2005, Gilliland 2002) Further, the RUNX1 mutation is mutually exclusive with CEBPA and NPM1 mutations, but closely associated with MLL/PTD.…”

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

“…14, 44 We also did not find a positive association between -7/del(7q) and RUNX1 mutation or a negative one between del(5q) and RUNX1 mutation as previously reported in myelodysplastic syndrome, 44 although a similar trend was noticeable. In fact, the only mutation associated with mutations in RUNX1 was trisomy 13, as observed by us and others.…”