Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis

Madison J. Kelly, Joan So, Amy J. Rogers, Gareth Gregory, Jason Li, Magnus Zethoven, Micah D. Gearhart, Vivian J. Bardwell, Ricky W. Johnstone, Stephin J. Vervoort and Lev M. Kats ()
Additional contact information
Madison J. Kelly: The Peter MacCallum Cancer Centre
Joan So: The Peter MacCallum Cancer Centre
Amy J. Rogers: The Peter MacCallum Cancer Centre
Gareth Gregory: The Peter MacCallum Cancer Centre
Jason Li: The Peter MacCallum Cancer Centre
Magnus Zethoven: The Peter MacCallum Cancer Centre
Micah D. Gearhart: University of Minnesota
Vivian J. Bardwell: University of Minnesota
Ricky W. Johnstone: The Peter MacCallum Cancer Centre
Stephin J. Vervoort: The Peter MacCallum Cancer Centre
Lev M. Kats: The Peter MacCallum Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09250-6

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