Abstract
A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.
Highlights
The transcription factor RUNX1 is a critical regulator of embryonic and adult hematopoiesis
The regulatory network between transcription factors, epigenetic cofactors and microRNAs is decisive for normal hematopoiesis
The transcription factor RUNX1 is important for the establishment of a megakaryocytic gene expression program and the concomitant repression of erythroid genes during megakaryocytic differentiation
Summary
The transcription factor RUNX1 (or AML1, acute myeloid leukemia 1) is a critical regulator of embryonic and adult hematopoiesis (reviewed in [1,2,3]). RUNX1 is involved in the t(8;21) chromosomal translocation found in approximately 15% of acute myeloid leukemia cases, where the DNA binding runt homology domain (RHD) of RUNX1 and almost the entire ETO (MTG8) protein are fused [10,11,12]. Similar to RUNX1, full length RUNX1/ETO has an inhibitory effect on erythropoiesis [5,22] Both RUNX1 and its leukemic fusion protein RUNX1/ETO influence expression of a number of microRNAs in normal differentiation and leukemia [23]. We posit that the disturbance of lineage differentiation such as erythropoiesis by RUNX1/ETO might be mediated through alterations of microRNA expression, in addition to the disturbance of transcriptional networks [24]. Because RUNX1 inhibits erythroid gene expression [5] and RUNX1/ETO interferes with erythroid differentiation [22], we were interested in downstream microRNAs at the megakaryocytic/erythroid bifurcation
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