Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Nat Cell Biol

Publication Date





1093 - 1104


Acetylation, Animals, CREB-Binding Protein, Cell Proliferation, Cell Self Renewal, Cell Transformation, Neoplastic, Cells, Cultured, DNA Damage, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Histones, Lymphangiogenesis, Lymphoid Progenitor Cells, Lymphoma, Lymphopoiesis, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplastic Stem Cells, Phenotype, Signal Transduction, Time Factors, Transcription, Genetic, Tumor Suppressor Protein p53