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We previously showed that RHOA deletions are enriched in progressing cases, but the role of RHOA deficiency is poorly defined despite its frequent occurrence in newly diagnosed disease. In this study, we show that RHOA loss downregulates CD19, promoting cell-intrinsic resistance to CAR-19 in vitro and in vivo. CD19 decline, however, provides an incomplete explanation of resistance and does not explain high frequency of the deletion in newly diagnosed cases. We therefore performed single-cell assessments of immunocompetent RHOA-deficient lymphoma microenvironments (LME), revealing remarkable concordance with features in CAR-19\u2013resistant patients. Despite increased microenvironmental production of interferon gamma, RHOA-deficient tumor cells themselves show an impaired response to the cytokine, including failed induction of class I MHC molecules. Overall, we describe for the first time how a single-gene alteration recurrent in CAR-19\u2013resistant lymphoma contributes to treatment failures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>RHOA loss of function, which predicts CAR T-cell treatment failure and is present in one in six newly diagnosed LBCL cases, impairs MHC class I display, reprograms LMEs, and downregulates CD19 to promote antigen escape. Del 3p21.31 is therefore a single-gene alteration in LBCL selected for immunotherapy resistance.<\/jats:p>\n                    <jats:p>See related commentary by Perkey and Kline, p. 852<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2643-3230.bcd-25-0482","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T13:01:58Z","timestamp":1789736518000},"page":"957-977","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>RHOA<\/i>\n                    Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR T\u2013Resistant Large B-cell Lymphomas"],"prefix":"10.1158","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-6539","authenticated-orcid":false,"given":"Austin D.","family":"Newsam","sequence":"first","affiliation":[{"name":"1Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, 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