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.

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Acknowledgements

The Huntly laboratory is funded by the ERC (grant 647685 COMAL), KKLF, MRC, Bloodwise, the Wellcome Trust (WT) and the Cambridge NIHR BRC. We acknowledge the WT/MRC centre grant (097922/Z/11/Z) and support from WT strategic award 100140. D.S. is a Postdoctoral Fellow of the Mildred-Scheel Organisation, German Cancer Aid. We thank C. Cossetti, M. Maj and R. Schulte at the CIMR Flow Cytometry Core for their help with cell sorting. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub. E.L. is funded by a Sir Henry Dale fellowship from the WT/Royal Society.

Author information

Affiliations

  1. Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, UK

    • Sarah J. Horton
    • , George Giotopoulos
    • , Haiyang Yun
    • , Shabana Vohra
    • , Olivia Sheppard
    • , Wai-In Chan
    • , Daniel Sasca
    • , Loukia Yiangou
    • , Hikari Osaki
    • , Faisal Basheer
    • , Paolo Gallipoli
    • , Ayşegül Erdem
    • , Anastasiya Sybirna
    • , Sarah Foerster
    • , Tonci Sustic
    • , Elisa Laurenti
    • , Daniel Hodson
    •  & Brian J. P. Huntly
  2. Department of Haematology, University of Cambridge, Cambridge, UK

    • Sarah J. Horton
    • , George Giotopoulos
    • , Haiyang Yun
    • , Shabana Vohra
    • , Olivia Sheppard
    • , Wai-In Chan
    • , Daniel Sasca
    • , Hikari Osaki
    • , Faisal Basheer
    • , Paolo Gallipoli
    • , Ayşegül Erdem
    • , Tonci Sustic
    • , Elisa Laurenti
    • , Daniel Hodson
    •  & Brian J. P. Huntly
  3. Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK

    • Sarah J. Horton
    • , George Giotopoulos
    • , Haiyang Yun
    • , Shabana Vohra
    • , Olivia Sheppard
    • , Rachael Bashford-Rogers
    • , Wai-In Chan
    • , Daniel Sasca
    • , Hikari Osaki
    • , Faisal Basheer
    • , Paolo Gallipoli
    • , Natalie Burrows
    • , Ayşegül Erdem
    • , Ken G. Smith
    • , Patrick Maxwell
    •  & Brian J. P. Huntly
  4. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

    • Mamunur Rashid
    •  & David J. Adams
  5. Department of Pathology, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK

    • Alexandra Clipson
    •  & Ming Q. Du
  6. Department of Pathology, Cambridge University Hospitals, Hills Road, Cambridge CB2 0QQ, UK

    • Wanfeng Zhao
    •  & Penny Wright
  7. Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK

    • Anna Petrunkina Harrison
  8. Barts Cancer Institute, Charterhouse Square, London EC1M 6BQ, UK

    • Jessica Okosun
    •  & Jude Fitzgibbon
  9. Department of Haematology, Cambridge University Hospitals, Hills Road, Cambridge CB2 0QQ, UK

    • Brian J. P. Huntly

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Contributions

S.J.H. designed and performed experiments, analysed data and wrote the paper. G.G. performed FACS, serial replating and transplantation experiments. H.Y. performed ChIP-Seq and qRT-PCR. S.V. performed bioinformatics analyses. O.S. maintained the mouse lines and performed experiments. R.B.-R. performed BCR amplification, sequencing and analysis. M.R. performed exome sequencing and bioinformatics analyses. A.C. designed and performed the allele-specific PCR. D.S. performed western blotting. L.Y. performed flow cytometry. W.-I.C., H.O., F.B., P.G., A.E., S.F. and T.S. provided technical assistance. N.B. and P.M. provided the CD19-Cre mice. A.S. optimized immunofluorescence experiments. W.Z. performed immunohistochemistry. A.P.H. and E.L. helped with design and sorting of HSPCs from patients. J.O. and J.F. provided patient samples. D.H. and K.G.S. designed experiments; P.W. analysed histology and immunohistochemistry. A.C. and M.Q.D. designed and analysed allele-specific PCR. D.J.A. analysed exome sequencing data. B.J.P.H. designed and analysed experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Brian J. P. Huntly.

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