Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia

Blood. 2010 Mar 4;115(9):1768-78. doi: 10.1182/blood-2009-08-240101. Epub 2009 Dec 22.

Abstract

Transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is essential for granulopoiesis and its function is deregulated in leukemia. Inhibition of E2F1, the master regulator of cell-cycle progression, by C/EBPalpha is pivotal for granulopoiesis. Recent studies show microRNA-223 (miR-223), a transcriptional target of C/EBPalpha, as a critical player during granulopoiesis. In this report, we demonstrate that during granulopoiesis microRNA-223 targets E2F1. E2F1 protein was up-regulated in miR-223 null mice. We show that miR-223 blocks cell-cycle progression in myeloid cells. miR-223 is down-regulated in different subtypes of acute myeloid leukemia (AML). We further show that E2F1 binds to the miR-223 promoter in AML blast cells and inhibits miR-223 transcription, suggesting that E2F1 is a transcriptional repressor of the miR-223 gene in AML. Our study supports a molecular network involving miR-223, C/EBPalpha, and E2F1 as major components of the granulocyte differentiation program, which is deregulated in AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Cycle
  • Cell Line
  • DNA Primers / genetics
  • Down-Regulation
  • E2F1 Transcription Factor / genetics*
  • E2F1 Transcription Factor / metabolism*
  • Feedback, Physiological
  • Granulocytes / metabolism
  • Granulocytes / pathology
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Leukopoiesis / genetics
  • Leukopoiesis / physiology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Models, Biological
  • Mutation
  • Up-Regulation

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • DNA Primers
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2f1 protein, mouse
  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs