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

Kazuki Okuyama, Tomokatsu Ikawa, Bernhard Gentner, Katsuto Hozumi, Ratanakanit Harnprasopwat, Jun Lu, Riu Yamashita, Daon Ha, Takae Toyoshima, Bidisha Chanda, Toyotaka Kawamata, Kazuaki Yokoyama, Shusheng Wang, Kiyoshi Ando, Harvey F. Lodish, Arinobu Tojo, Hiroshi Kawamoto, Ai Kotani

Research output: Contribution to journalArticle

Abstract

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 Bcell 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 enhancerbinding 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.

Original languageEnglish
Pages (from-to)13410-13415
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
Publication statusPublished - Aug 13 2013

Keywords

  • Cell fate decision
  • Lymphopoiesis

ASJC Scopus subject areas

  • General

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  • Cite this

    Okuyama, K., Ikawa, T., Gentner, B., Hozumi, K., Harnprasopwat, R., Lu, J., Yamashita, R., Ha, D., Toyoshima, T., Chanda, B., Kawamata, T., Yokoyama, K., Wang, S., Ando, K., Lodish, H. F., Tojo, A., Kawamoto, H., & Kotani, A. (2013). MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors. Proceedings of the National Academy of Sciences of the United States of America, 110(33), 13410-13415. https://doi.org/10.1073/pnas.1220710110