Abstract
BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with upregulated expression of Hox genes. Mutation of Bcor reduced protein levels of RING1B, an H2A ubiquitin ligase subunit of PRC1 family complexes and reduced H2AK119ub upstream of upregulated HoxA genes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with enhanced cell proliferation and myeloid differentiation. Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes.
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Acknowledgements
We thank Dimitris Kioussis for sharing the Vav-iCre allele. This work was funded by the National Institutes of Health, USA (NIH; Grant No. R01CA026038-35 (HPK) and 5R01CA071540 (VJB)), the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award to HPK and the NMRC Centre Grant awarded to National University Cancer Institute of Singapore, the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives. Further thanks is given to Reuben Yeroushalmi, Blanche and Steven Koegler. Additional funding came from the Minnesota Masonic Charities, the University of Minnesota OVPR and the Leukemia Research Fund (VJB).
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Cao, Q., Gearhart, M., Gery, S. et al. BCOR regulates myeloid cell proliferation and differentiation. Leukemia 30, 1155–1165 (2016). https://doi.org/10.1038/leu.2016.2
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DOI: https://doi.org/10.1038/leu.2016.2
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