High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia

Abstract

A high incidence of somatically acquired point mutations in the AML1/RUNX1 gene has been reported in poorly differentiated acute myeloid leukemia (AML, M0) and in radiation-associated and therapy-related myelodysplastic syndrome (MDS) or AML. The vast majority of AML1 mutations identified in these diseases were localized in the amino (N)-terminal region, especially in the DNA-binding Runt homology domain. In this report, we show that AML1 point mutations were found in 26 (23.6%) of 110 patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt), and AML following MDS (defined these 3 disease categories as MDS/AML). Among them, 9 (8.2%) mutations occurred in the carboxy (C)-terminal region, which were exclusively found in MDS/AML and were strongly correlated with sporadic MDS/AML. All patients with MDS/AML with an AML1 mutation expressed wild-type AML1 protein and had a significantly worse prognosis than those without AML1 mutations. Most AML1 mutants lost trans-activation potential, regardless of their DNA binding potential. These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopatho-

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

“…19 We found BM mononuclear cells from MDS/AML patients harboring RUNX1-C-terminal mutations had significantly lower GAD-D45A expression compared with those from MDS/AML patients with WT RUNX1 (P ¼ 0.0233; Figure 6). …”

“…19,38,39 We speculate that a RUNX1 mutation may be a cause of additional mutation(s) through the impaired DDR response. In future studies, whole genome analysis of MDS/AML samples harboring RUNX1 mutations would clarify the role of RUNX1 mutations in the occurrence of genetic abnormalities in these patients.…”

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

“…C-terminal mutations are seen at lower frequency and almost exclusively in MDS or AML following MDS, and seem to be associated with poor prognosis. 132 A high frequency (40%) of N-terminal AML1 mutation has also been observed in t-AML and t-MDS. 132 Some monoallelic mutations may act in a dominant-negative manner through inhibition of the effects the remaining WT AML1.…”

“…132 A high frequency (40%) of N-terminal AML1 mutation has also been observed in t-AML and t-MDS. 132 Some monoallelic mutations may act in a dominant-negative manner through inhibition of the effects the remaining WT AML1. This hypothesis was confirmed by Osato et al and Imai et al, 124,126 who demonstrated that some AML1 gene missense mutation cotransfected with WT AML1 abolished transactivation of the M-CSF receptor promoter.…”

Myeloid neoplasms with germ line RUNX1 mutation

“…Indeed, RUNX1 mutations have frequently been identified in patients with MDS and AML [6,7]. Furthermore, a higher frequency of RUNX1 mutations (30-50%) has been reported in therapyrelated and radiation-associated MDS and AML [13][14][15]. In general, RUNX1 mutations are considered to result in the loss of RUNX1 functions.…”