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 Kras G12D 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.
Bibliographical noteFunding Information:
We thank the Peter MacCallum Cancer Centre Flow Cytometry, Molecular Genomics and Animal core facilities for their contribution. We would also like to thank the Leu-cegene group (https://leucegene.ca/) for providing mutational data to facilitate RNAseq analysis of AML patient samples. L.M.K. and R.J.W. are supported by funding from the Victorian Cancer Agency and the National Health and Medical Research Council of Australia. V.J.B. is supported by funding from the NIH (NCI R01CA071540 and NIH NICHD R01HD084459).