Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis

Abstract

The BCL6 Corepressor (BCOR) is a component of a variant Polycomb repressive complex 1 (PRC1) that is essential for normal development. Recurrent mutations in the BCOR gene have been identified in acute myeloid leukaemia and myelodysplastic syndrome among other cancers; however, its function remains poorly understood. Here we examine the role of BCOR in haematopoiesis in vivo using a conditional mouse model that mimics the mutations observed in haematological malignancies. Inactivation of Bcor in haematopoietic stem cells (HSCs) results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Gene expression analysis and chromatin immunoprecipitation sequencing reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors such as Hoxa7/9. This study provides mechanistic understanding of how BCOR regulates cell fate decisions and how loss of function contributes to the development of leukaemia.

Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer

“…This limited evidence of cancer driver mutations in genes encoding cPRC1 subunits might be related to the high level of redundancy among cPRC1 subunits, which would limit the impact of mutations. However, somatic mutations in the ncPRC1 subunit BCOR have been identified in AML and myelodysplastic syndrome, and mouse studies support a tumor suppressor function in leukemia (Damm et al 2013;Tanaka et al 2017;Kelly et al 2019). Bcor has a key function in the regulation of the hematopoietic stem cell transcription network and its inactivation drives expansion of myeloid progenitor cells and cooperates with oncogenic Kras to drive the development of leukemia (Kelly et al 2019).…”

“…However, somatic mutations in the ncPRC1 subunit BCOR have been identified in AML and myelodysplastic syndrome, and mouse studies support a tumor suppressor function in leukemia (Damm et al 2013;Tanaka et al 2017;Kelly et al 2019). Bcor has a key function in the regulation of the hematopoietic stem cell transcription network and its inactivation drives expansion of myeloid progenitor cells and cooperates with oncogenic Kras to drive the development of leukemia (Kelly et al 2019). Thus, while the roles of some PRC1 components in cancer seems mostly related to their requirement for stem cell survival, BCOR appears to be a bona fide tumor suppressor.…”

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

“…The disruptive nature of these mutations that usually results in a premature stop codon and non-sense mediated decay or protein truncation are consistent with a tumor-suppressive role of the Bcor gene in myeloid malignancies. Accordingly, mice lacking Bcor exons 9 and 10, which encode for a carboxyl-terminal truncated Bcor unable to interact with the PCR1 core effector components, are characterized by expansion of myeloid progenitors [17], enhanced cell proliferation, and myeloid differentiation associated with upregulation of HoxA cluster [18].…”

“…However, Bcor deficiency is not itself sufficient to promote leukemia [17,18], strongly suggesting that other mutations are required to induce myeloid malignancies. The type of myeloid neoplasm developing in Bcor-deficient mouse may vary depending on the co-occurring genetic lesions.…”

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

“…Currently, the molecular basis of PHACE syndrome is unknown but is suspected to involve somatic mosaic mutation, a phenomenon that has been described in mothers of affected daughters with OFCD [19]. Given that infantile hemangioma is a benign neoplasm that exceedingly rarely transforms to angiosarcoma, along with the recognition that BCOR functions as a tumor suppressor gene implicated in sarcomas as well as some hematologic malignancies (with one reported case of T-cell lymphoma reported in a male with Lenz microphthalmia [4]), systematic investigation of BCOR and PHACE patients may provide important insights into human development and tumorigenesis [20]. BCOR copy number reductions and focal deletions have been reported rarely in retinoblastomas, especially occurring later in childhood [21,22].…”