title: 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.
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Q
authors: Q
authors: Cao
authors: Department of Genetics, Cell Biology and Development and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors: M D
authors: MD
authors: Gearhart
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: S
authors: S
authors: Gery
authors: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
authors: S
authors: S
authors: Shojaee
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: H
authors: H
authors: Yang
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: H
authors: H
authors: Sun
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: D-C
authors: DC
authors: Lin
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Changjiang Scholar's Laboratory and Cancer Research Center, Shantou University Medical College, Shantou, China.
authors: J-W
authors: JW
authors: Bai
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: M
authors: M
authors: Mead
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Z
authors: Z
authors: Zhao
authors: Department of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Q
authors: Q
authors: Chen
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: W-W
authors: WW
authors: Chien
authors: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: S
authors: S
authors: Alkan
authors: MLL Munich Leukemia Laboratory, Munich, Germany.
authors: T
authors: T
authors: Alpermann
authors: MLL Munich Leukemia Laboratory, Munich, Germany.
authors: T
authors: T
authors: Haferlach
authors: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
authors: M
authors: M
authors: Müschen
authors: Department of Genetics, Cell Biology and Development and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors: V J
authors: VJ
authors: Bardwell
authors: Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute of Singapore, National University Hospital, Singapore.
authors: H P
authors: HP
authors: Koeffler
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D005801:Genes, Homeobox / Q000235:genetics; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D063150:Polycomb Repressive Complex 1 / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C553467:Bcor protein, mouse; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1