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, Ari M Melnick
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...
April 3, 2024: Nature Communications