Novel loss‐of‐function mutations of the haematopoiesis‐related transcription factor, acute myeloid leukaemia 1/runt‐related transcription factor 1, detected in acute myeloblastic leukaemia and myelodysplastic syndrome

Abstract

Summary AML1/RUNX1, which encodes a transcription factor essential for definitive haematopoiesis, is a frequent target of leukaemia‐associated chromosome translocations. Point mutations of this gene have also recently been associated with leukaemia and myelodysplastic syndrome (MDS). To further define the frequency and biological characteristics of AML1 mutations, we have examined 170 cases of such diseases. Mutations within the runt‐domain were identified in five cases: one of de novo acute myeloid leukaemia (AML) and four of MDS. Where multiple time point samples were available, mutations were detected in the earliest samples, which persisted throughout the disease course. Of the five mutations, one was a silent mutation, two were apparent loss‐of‐function mutations caused by N‐terminal truncation, and two were insertions, I150ins and K168ins, which preserved most of the AML1 DNA‐binding domain. Both AML1 molecules with insertion mutations were non‐functional in that they were unable to rescue haematological defects in AML1‐deficient mouse embryonic stem cells. In addition, activating mutations of N‐ras, deletion of chromosome 12p, or inactivation of TP53 accompanied some of the AML1 mutations. Together, these observations strongly suggest that one‐allele inactivation of AML1 serves as an initial or early event that plays an important role in the eventual development of overt diseases with additional genetic alterations.

Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients

“…8 The recent report that, in MDS and AML studied sequentially, AML1 mutations were found early whereas RAS mutations only occurred in the latest samples may strengthen this multistep hypothesis in leukaemogenesis. 22 The propensity of FPD (Familial Platelet Disease) patients to develop acute leukaemia and the higher frequency of FLT3 mutation at relapse in AML as compared to diagnosis also support this hypothesis. 23 Those perturbations largely results from deregulation of genes involved in cell maintenance and DNA repair.…”

RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation

“…11,12 RUNX1 mutations have been described in the M0 subtype of AML, 13,14 radiation-associated and chemotherapy-related MDS or AML, 15,16 or in patients with de novo high-risk MDS; [17][18][19] however, only a small number of patients with CMML have been examined for RUNX1 mutations, 20 and the frequency and patterns of RUNX1 mutations in CMML remain to be defined. In this study, we analyzed a large cohort of patients with CMML to define the prevalence and types of RUNX1 mutations.…”

Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome

“…However, abnormalities in these genes are predominantly found in patients with high-risk but not low-risk disease. [17][18][19]24 Analysis of marrow from MDS patients with chromosomal abnormalities has shown the abnormal karyotype is present in either the hematopoietic stem-cell (HSC) or early committed myeloid progenitor. 25,26 In keeping with a stem/myeloid progenitor defect, there is reduced in vitro long-term culture-initiating cell activity 27 and decreased numbers of erythroid, granulocyte, and megakaryocyte colonies.…”

“…[9][10][11][12][13][14][15][16] However, it is not clear if increased apoptosis is the primary event in early MDS or merely a pathophysiologic response to excessive progenitor-cell proliferation. The second, cell-intrinsic theory, hypothesizes that the primary abnormalities are genetic or epigenetic changes in key transcription factors, [17][18][19] signal transduction pathway components, 20,21 DNA repair machinery, 22 and cell-cycle regulators, 23 resulting in altered hematopoietic proliferation and differentiation. However, abnormalities in these genes are predominantly found in patients with high-risk but not low-risk disease.…”