Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B cell fate decisions and yields T cell-depleted lymphomas.

TitleCooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B cell fate decisions and yields T cell-depleted lymphomas.
Publication TypeJournal Article
Year of Publication2023
AuthorsLi J, Chin CR, Ying H-Y, Meydan C, Teater MR, Xia M, Farinha P, Takata K, Chu C-S, Rivas MA, Chadburn A, Steidl C, Scott DW, Roeder RG, Mason CE, B├ęguelin W, Melnick AM
JournalbioRxiv
Date Published2023 Feb 13
Abstract

UNLABELLED: Mutations affecting enhancer chromatin regulators CREBBP and KMT2D are highly co-occurrent in germinal center (GC)-derived lymphomas and other tumors, even though regulating similar pathways. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d (C+K) indeed accelerated lymphomagenesis. C+K haploinsufficiency induced GC hyperplasia by altering cell fate decisions, skewing B cells away from memory and plasma cell differentiation. C+K deficiency particularly impaired enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for immunoregulatory and differentiation genes. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other's stable recruitment to enhancers. Notably, C+K lymphomas in mice and humans manifested significantly reduced CD8 + T-cell abundance. Hence, deficiency of C+K cooperatively induced an immune evasive phenotype due at least in part to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions.

SIGNIFICANCE: Although CREBBP and KMT2D have similar enhancer regulatory functions, they are paradoxically co-mutated in lymphomas. We show that their combined loss causes specific disruption of super-enhancers driving immune synapse genes. Importantly, this leads to reduction of CD8 cells in lymphomas, linking super-enhancer function to immune surveillance, with implications for immunotherapy resistance.

DOI10.1101/2023.02.13.528351
Alternate JournalbioRxiv
PubMed ID36824887
PubMed Central IDPMC9949106
Grant ListR01 AI148387 / AI / NIAID NIH HHS / United States
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Amy Chadburn, M.D.

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