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2776 Cooperative Super-Enhancer Inactivation through Loss of Crebbp and KMT2D Skews B Cell Fate Decisions and Yields T Cell-Depleted Lymphomas

Program: Oral and Poster Abstracts
Session: 603. Lymphoid Oncogenesis: Basic: Poster II
Hematology Disease Topics & Pathways:
Poster-only abstracts
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Jie Li1*, Christopher Chin, PhD1*, Hsia-Yuan Ying1*, Cem Meydan2*, Matthew Teater, PhD3*, Min Xia, PhD3, Pedro Farinha4, Katsuyoshi Takata4*, Chi-Shuen Chu5*, Martin A Rivas, PhD, MS1, Amy Chadburn, MD6, Christian Steidl, MD, PhD7, David W. Scott, MBChB, PhD8, Robert G. Roeder5*, Christopher Mason2*, Wendy Beguelin, PhD9* and Ari M Melnick, MD3

1Department of Medicine, Weill Cornell Medicine, New York, NY
2Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY
3Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
4BC Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada
5The Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY
6Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
7Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
8Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada
9Department of Medicine, Weill Cornell Medical College, New York, NY

Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that most of these lymphoma mutations induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D, even though regulating overlapping gene enhancers and pathways. Hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d (C+K) do indeed induce a more severe lymphoma phenotype (vs either allele alone) and unexpectedly conferred an immune evasive phenotype manifesting as reduced CD8+ T cell infiltration. This was linked to profound repression of immune synapse genes that provide costimulatory effects to T-cells and others. Repression of immune synapse genes was reflected in impaired response to T-cell directed cell fate decisions and weakening of costimulatory signals. From the epigenetic perspective we observed interaction and mutually dependent cooperative binding of C+K to chromatin. Notably loss of C+K cooperativity was selectively severe at superenhancers (vs enhancers), especially those driving expression of immune synapse signaling genes and pointing to a particular dependency for both co-activators at these specialized regulatory elements. Therefore, we show that critical features of the lymphoma microenvironment are shaped by specific combinations of chromatin modifier somatic mutations, induced by the dependency of immune synapse superenhancers on cooperative actions of CREBBP and KMT2D.

Disclosures: Chadburn: Leica Biosystems: Consultancy; Boehringer Ingelheim Pharmaceuticals, Inc.: Consultancy; Medical College of Wisconsin: Honoraria. Steidl: Seattle Genetics, AbbVie, and Bayer: Consultancy; Bristol Myers Squibb, Epizyme and Trillium Therapeutics Inc.: Research Funding. Scott: Abbvie, AstraZeneca, Incyte: Consultancy; Janssen and Roche: Research Funding. Mason: Abbvie, ArcBio, Daiichi Sankyo, DNA Genotek, Tempus Labs, and Whole Biome: Other: an advisor or grantee; Biotia and Onegevity Health: Membership on an entity's Board of Directors or advisory committees. Melnick: Daiichi Sankyo: Consultancy, Research Funding; Janssen: Research Funding; Treeline Biosciences: Consultancy; Ipsen: Consultancy, Research Funding.

*signifies non-member of ASH