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Cbfb deficiency results in differentiation blocks and stem/progenitor cell expansion in hematopoiesis

Leukemia volume 29, pages 753–757 (2015)Cite this article

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The PEBP2/CBF heterodimeric transcription factors consist of two subunits: the DNA-binding α subunit and the non-DNA-binding β subunit. The β subunit, Cbfβ, encoded by the Cbfb gene, serves to increase the DNA binding ability of the α subunit in an allosteric manner and protects it from protein degradation. The α subunit is encoded by three distinct Runx genes: Runx1, Runx2 and Runx3. Of these, Runx1 is well established as an important regulator of hematopoiesis. Consistent with Cbfβ being indispensible for Runx1 function, Cbfb−/− murine embryos showed the same spectrum of abnormalities found in Runx1−/− embryos: Cbfb−/− embryos die at embryonic day (E) 12.5 due to hemorrhage in the central nervous system accompanied by the inability to generate hematopoietic stem cells (HSCs).1 At the adult stage, Runx1 conditional knockout (cKO) mice led to an expanded HSC compartment and subsequent stem cell exhaustion.2, 3 In addition, Runx1 cKO mice show differentiation blocks in megakaryocyte and lymphocyte lineages.3, 4 Due to the embryonic lethality of Cbfb−/− mice, Cbfb function in adult hematopoiesis has not been investigated.

RUNX1 and CBFB are frequent targets of mutations in human leukemia. Approximately 30% of acute leukemia carry RUNX1 genetic alterations, such as chromosomal translocations and point mutations,5, 6, 7 resulting in loss of RUNX1 activity. CBFB is altered in an inversion of chromosome 16, inv(16)(p13q22), or the less common t(16;16)(p13;q22), generating the CBFB-MYH11 fusion gene associated with the M4Eo subtype of AML.8 Cbfb-MYH11 knock-in (KI) mice developed phenotypes that are indistinguishable from Cbfb−/− or Runx1−/− mice,9 indicating the fusion gene product, CBFβ-SMMHC protein, acts as a dominant repressor of PEBP2/CBF function.

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Acknowledgements

We thank M Mok, C Chung and HF Tan for their technical assistance; K Rajewshky for Mx-Cre Tg mice; and members of MD2 Vivarium, NUS, for mouse husbandry. This work was supported by A*STAR (Agency of Science, Technology and Research), Biomedical Research Council, National Medical Research Council, National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

Author Contributions

CQW and DWC performed experiments, analyzed data and wrote the manuscript; JYC performed experiments and analyzed data; CWJ and IT provided research tools; VT and MO designed research and wrote the manuscript; and all authors reviewed and approved the manuscript.

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Author notes

  1. C Q Wang, D W L Chin and J Y Chooi: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    C Q Wang, D W L Chin, J Y Chooi, W J Chng & M Osato

  2. Institute of Molecular and Cell Biology, Singapore

    C Q Wang & V Tergaonkar

  3. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    I Taniuchi

  4. Institute of Bioengineering and Nanotechnology, Singapore

    M Osato

  5. Department of Paediatrics, National University of Singapore, Singapore

    M Osato

  6. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    M Osato

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  1. C Q Wang
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Correspondence to V Tergaonkar or M Osato.

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Wang, C., Chin, D., Chooi, J. et al. Cbfb deficiency results in differentiation blocks and stem/progenitor cell expansion in hematopoiesis. Leukemia 29, 753–757 (2015). https://doi.org/10.1038/leu.2014.316

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