Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis.
Madison J KellyJoan SoAmy J RogersGareth Peter GregoryJason LiMagnus ZethovenMicah D GearhartVivian J BardwellRicky W JohnstoneStephin J VervoortLev M KatsPublished in: Nature communications (2019)
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.
Keyphrases
- clear cell
- genome wide identification
- transcription factor
- genome wide
- stem cells
- liver failure
- dendritic cells
- mouse model
- bone marrow
- acute myeloid leukemia
- cell fate
- respiratory failure
- copy number
- drug induced
- gene expression
- dna damage
- single cell
- long non coding rna
- oxidative stress
- long noncoding rna
- genome wide analysis
- intensive care unit
- young adults
- mechanical ventilation