Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

TitleLoss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.
Publication TypeJournal Article
Year of Publication2024
AuthorsLi J, Chin CR, Ying H-Y, Meydan C, Teater MR, Xia M, Farinha P, Takata K, Chu C-S, Jiang Y, Eagles J, Passerini V, Tang Z, Rivas MA, Weigert O, Pugh TJ, Chadburn A, Steidl C, Scott DW, Roeder RG, Mason CE, Zappasodi R, B├ęguelin W, Melnick AM
JournalNat Commun
Volume15
Issue1
Pagination2879
Date Published2024 Apr 03
ISSN2041-1723
KeywordsAnimals, B-Lymphocytes, Chromatin, Germinal Center, Lymphoma, Large B-Cell, Diffuse, Mice, Mutation, Tumor Microenvironment
Abstract

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

DOI10.1038/s41467-024-47012-1
Alternate JournalNat Commun
PubMed ID38570506
PubMed Central IDPMC10991284
Grant ListR01 CA270245 / CA / NCI NIH HHS / United States
P01 CA214274 / CA / NCI NIH HHS / United States
F31 CA254302 / CA / NCI NIH HHS / United States
R01 CA249054 / CA / NCI NIH HHS / United States
R01 AI148387 / AI / NIAID NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
R01 MH117406 / MH / NIMH NIH HHS / United States
Related Faculty: 
Amy Chadburn, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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