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

Jie Li, Christopher R. Chin, Hsia-Yuan Ying, Cem Meydan, Matthew R. Teater, Min Xia, Pedro Farinha, Katsuyoshi Takata, Chi-Shuen Chu, Yiyue Jiang, Jenna Eagles, Verena Passerini, Zhanyun Tang, Martin A. Rivas, Oliver Weigert, Trevor J. Pugh, Amy Chadburn, Christian Steidl, David W. Scott, Robert G. Roeder, Christopher E. Mason, Roberta Zappasodi, Wendy Béguelin () and Ari M. Melnick ()
Additional contact information
Jie Li: Cornell University
Christopher R. Chin: Cornell University
Hsia-Yuan Ying: Cornell University
Cem Meydan: Weill Cornell Medicine
Matthew R. Teater: Cornell University
Min Xia: Cornell University
Pedro Farinha: University of British Columbia
Katsuyoshi Takata: British Columbia Cancer
Chi-Shuen Chu: The Rockefeller University
Yiyue Jiang: University Health Network
Jenna Eagles: University Health Network
Verena Passerini: Ludwig-Maximilians University (LMU) Hospital
Zhanyun Tang: The Rockefeller University
Martin A. Rivas: Cornell University
Oliver Weigert: Ludwig-Maximilians University (LMU) Hospital
Trevor J. Pugh: University Health Network
Amy Chadburn: Weill Cornell Medicine
Christian Steidl: British Columbia Cancer
David W. Scott: University of British Columbia
Robert G. Roeder: The Rockefeller University
Christopher E. Mason: Weill Cornell Medicine
Roberta Zappasodi: Cornell University
Wendy Béguelin: Cornell University
Ari M. Melnick: Cornell University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47012-1

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