Cargando…
Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis
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...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430802/ https://www.ncbi.nlm.nih.gov/pubmed/30902969 http://dx.doi.org/10.1038/s41467-019-09250-6 |
_version_ | 1783405820273229824 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Kelly, Madison J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6430802 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64308022019-03-25 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. Nat Commun Article 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. Nature Publishing Group UK 2019-03-22 /pmc/articles/PMC6430802/ /pubmed/30902969 http://dx.doi.org/10.1038/s41467-019-09250-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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 |
title | Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
title_full | Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
title_fullStr | Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
title_full_unstemmed | Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
title_short | Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
title_sort | bcor loss perturbs myeloid differentiation and promotes leukaemogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430802/ https://www.ncbi.nlm.nih.gov/pubmed/30902969 http://dx.doi.org/10.1038/s41467-019-09250-6 |
work_keys_str_mv | AT kellymadisonj bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT sojoan bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT rogersamyj bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT gregorygareth bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT lijason bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT zethovenmagnus bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT gearhartmicahd bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT bardwellvivianj bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT johnstonerickyw bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT vervoortstephinj bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis AT katslevm bcorlossperturbsmyeloiddifferentiationandpromotesleukaemogenesis |