| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-22 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-47012-1 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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