Dataset Information

BCOR regulates myeloid cell proliferation and differentiation.

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.

SUBMITTER: Cao Q

PROVIDER: S-EPMC5131645 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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BCOR regulates myeloid cell proliferation and differentiation.

Cao Q Q Gearhart M D MD Gery S S Shojaee S S Yang H H Sun H H Lin D-C DC Bai J-W JW Mead M M Zhao Z Z Chen Q Q Chien W-W WW Alkan S S Alpermann T T Haferlach T T Müschen M M Bardwell V J VJ Koeffler H P HP

Leukemia 20160205 5

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 hig ...[more]

PMID: 26847029

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Project description:BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1) complex. Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukaemia (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 cell models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with reduced protein levels of RING1B, a ubiquitin ligase subunit of PRC1 family complexes. 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 proliferation and myeloid differentiation and decreased stem cell quiescence. Further, we used a MLL-AF9 murine model of AML and found that loss of Bcor increased serial replating efficiency, enhanced MLL-AF9 in blocking cell differentiation, and increased expression of Evi1 which is associated with leukemic transformation. Our results strongly suggest that BCOR plays an indispensable role in maintaining hematopoietic stem cell (HSC) quiescence by inhibiting myeloid stem cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. We took advantage of a mouse conditional Bcor allele which has exons 9 and 10 been flanked by LoxP sites to allow their removal via expression of Cre recombinase. Excision of these exons results in a frame shift and a premature stop codon causing nonsense mediated decay and/or carboxy-terminal deletion of the BCOR protein. CD34+ cells were sorted from control or Bcor mutant cells cultured under myeloid stem/progenitor conditions (IL3, 6 and SCF). We used microarrays to detail the global programme of gene expression in Control and Bcor mutant CD34+ cells.

Dataset Information

BCOR regulates myeloid cell proliferation and differentiation.

Publications

BCOR regulates myeloid cell proliferation and differentiation.

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