Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors

Horton SJ, Giotopoulos G, Yun H, Vohra S, Sheppard O, Bashford-Rogers R, Rashid M, Clipson A, Chan WI, Sasca D, Yiangou L, Osaki H, Basheer F, Gallipoli P, Burrows N, Erdem A, Sybirna A, Foerster S, Zhao W, Sustic T, Harrison AP, Laurenti E, Okosun J, Hodson D, Wright P, Smith KG, Maxwell P, Fitzgibbon J, Du MQ, Adams DJ, Huntly BJP (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Nature Cell Biology Nature Research

Book Volume: 19

Pages Range: 1093-1104

Journal Issue: 9

DOI: 10.1038/ncb3597

Abstract

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

Additional Organisation(s)

Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

University of Cambridge GB United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) Barts Cancer Institute GB United Kingdom (GB) Cambridge University Hospital GB United Kingdom (GB)

How to cite

APA:

Horton, S.J., Giotopoulos, G., Yun, H., Vohra, S., Sheppard, O., Bashford-Rogers, R.,... Huntly, B.J.P. (2017). Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors. Nature Cell Biology, 19(9), 1093-1104. https://dx.doi.org/10.1038/ncb3597

MLA:

Horton, Sarah J., et al. "Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors." Nature Cell Biology 19.9 (2017): 1093-1104.

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