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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,3,14]]},"abstract":"<jats:p>\n                    Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB\/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)\u2013specific haploinsufficiency of\n                    <jats:italic>Crebbp<\/jats:italic>\n                    and\n                    <jats:italic>Kmt2d<\/jats:italic>\n                    synergizes in\u00a0vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers\/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual\n                    <jats:italic>Crebbp<\/jats:italic>\n                    \/\n                    <jats:italic>Kmt2d<\/jats:italic>\n                    loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL\/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL\/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2218330120","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T14:09:04Z","timestamp":1678370944000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells"],"prefix":"10.1073","volume":"120","author":[{"given":"Sofija","family":"Vlasevska","sequence":"first","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Garcia-Ibanez","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Duval","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony\u00a0B.","family":"Holmes","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahat","family":"Jahan","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Cai","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongwei","family":"Mo","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Basso","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"},{"name":"Department of Pathology and Cell Biology, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4556-4358","authenticated-orcid":false,"given":"Rajesh\u00a0K.","family":"Soni","sequence":"additional","affiliation":[{"name":"Proteomics and Macromolecular Crystallography Shared Resource, Columbia University, New York, NY 10032"},{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6250-048X","authenticated-orcid":false,"given":"Govind","family":"Bhagat","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University, New York, NY 10032"},{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Dalla-Favera","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"},{"name":"Department of Pathology and Cell Biology, Columbia University, New York, NY 10032"},{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032"},{"name":"Department of Genetics and Development, Columbia\u00a0University, New York, NY 10032"},{"name":"Department of Microbiology and Immunology, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6819-7370","authenticated-orcid":false,"given":"Laura","family":"Pasqualucci","sequence":"additional","affiliation":[{"name":"Institute for Cancer Genetics, Columbia University, New York, NY 10032"},{"name":"Department of Pathology and Cell Biology, Columbia University, New York, NY 10032"},{"name":"Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","unstructured":"L. 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