Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias

Blood. 2014 Aug 28;124(9):1502-12. doi: 10.1182/blood-2014-02-553842. Epub 2014 Jul 8.

Abstract

The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Female
  • Gene Deletion
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Interferon Regulatory Factors / antagonists & inhibitors
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism*
  • Leukemia, B-Cell / etiology
  • Leukemia, B-Cell / genetics*
  • Leukemia, B-Cell / metabolism*
  • Leukemia, Myeloid / etiology
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Up-Regulation

Substances

  • Interferon Regulatory Factors
  • MIRN125 microRNA, human
  • MicroRNAs
  • Mirn125 microRNA, mouse
  • RNA, Messenger
  • RNA, Neoplasm
  • interferon regulatory factor-4