MiR144/451 Expression Is Repressed by RUNX1 During Megakaryopoiesis and Disturbed by RUNX1/ETO

PLoS Genet. 2016 Mar 18;12(3):e1005946. doi: 10.1371/journal.pgen.1005946. eCollection 2016 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / genetics
  • Cell Lineage
  • Core Binding Factor Alpha 2 Subunit / biosynthesis
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Gene Expression Regulation, Leukemic
  • Gene Regulatory Networks / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Megakaryocytes / cytology
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Oncogene Proteins, Fusion / biosynthesis
  • Oncogene Proteins, Fusion / genetics*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • MIRN451 microRNA, human
  • MicroRNAs
  • Oncogene Proteins, Fusion
  • RUNX1 protein, human

Grant support

This work was supported by the DFG, LA-1389/6-1 and DFG, SPP-1463, LA-1389/5-2) to JL http://www.dfg.de and by the LOEWE Center for Cell and Gene Therapy HMWK, III L 4-518/17.004, 20113 http://www.cgt-frankfurt.de/Default.aspx. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.