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, Lev M. Kats

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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 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.

Original languageEnglish
Article number1347
Number of pages14
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 22 Mar 2019

Cite this

Kelly, M. J., So, J., Rogers, A. J., Gregory, G., Li, J., Zethoven, M., ... Kats, L. M. (2019). Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis. Nature Communications, 10(1), [1347]. https://doi.org/10.1038/s41467-019-09250-6
Kelly, Madison J. ; So, Joan ; Rogers, Amy J. ; Gregory, Gareth ; Li, Jason ; Zethoven, Magnus ; Gearhart, Micah D. ; Bardwell, Vivian J. ; Johnstone, Ricky W. ; Vervoort, Stephin J. ; Kats, Lev M. / Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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 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.",
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Kelly, MJ, So, J, Rogers, AJ, Gregory, G, Li, J, Zethoven, M, Gearhart, MD, Bardwell, VJ, Johnstone, RW, Vervoort, SJ & Kats, LM 2019, 'Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis', Nature Communications, vol. 10, no. 1, 1347. https://doi.org/10.1038/s41467-019-09250-6

Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis. / Kelly, Madison J.; So, Joan; Rogers, Amy J.; Gregory, Gareth; Li, Jason; Zethoven, Magnus; Gearhart, Micah D.; Bardwell, Vivian J.; Johnstone, Ricky W.; Vervoort, Stephin J.; Kats, Lev M.

In: Nature Communications, Vol. 10, No. 1, 1347, 22.03.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bardwell, Vivian J.

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AU - Kats, Lev M.

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