MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13410-5. doi: 10.1073/pnas.1220710110. Epub 2013 Jul 26.


Lineage specification is thought to be largely regulated at the level of transcription, where lineage-specific transcription factors drive specific cell fates. MicroRNAs (miR), vital to many cell functions, act posttranscriptionally to decrease the expression of target mRNAs. MLL-AF4 acute lymphocytic leukemia exhibits both myeloid and B-cell surface markers, suggesting that the transformed cells are B-cell myeloid progenitor cells. Through gain- and loss-of-function experiments, we demonstrated that microRNA 126 (miR-126) drives B-cell myeloid biphenotypic leukemia differentiation toward B cells without changing expression of E2A immunoglobulin enhancer-binding factor E12/E47 (E2A), early B-cell factor 1 (EBF1), or paired box protein 5, which are critical transcription factors in B-lymphopoiesis. Similar induction of B-cell differentiation by miR-126 was observed in normal hematopoietic cells in vitro and in vivo in uncommitted murine c-Kit(+)Sca1(+)Lineage(-) cells, with insulin regulatory subunit-1 acting as a target of miR-126. Importantly, in EBF1-deficient hematopoietic progenitor cells, which fail to differentiate into B cells, miR-126 significantly up-regulated B220, and induced the expression of B-cell genes, including recombination activating genes-1/2 and CD79a/b. These data suggest that miR-126 can at least partly rescue B-cell development independently of EBF1. These experiments show that miR-126 regulates myeloid vs. B-cell fate through an alternative machinery, establishing the critical role of miRNAs in the lineage specification of multipotent mammalian cells.

Keywords: cell fate decision; lymphopoiesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cell Line, Tumor
  • Cell Lineage / genetics*
  • Cell Lineage / immunology
  • DNA Primers
  • Gene Expression Profiling*
  • Genetic Vectors / genetics
  • Humans
  • Leukemia, B-Cell / metabolism*
  • Luciferases
  • MicroRNAs / metabolism*
  • Myeloid Progenitor Cells
  • Oligonucleotides / genetics
  • Statistics, Nonparametric
  • Trans-Activators / metabolism
  • Transcription Factor 3 / metabolism


  • DNA Primers
  • EBF1 protein, human
  • MIRN126 microRNA, mouse
  • MicroRNAs
  • Oligonucleotides
  • Trans-Activators
  • Transcription Factor 3
  • Luciferases