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Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy.<\/jats:p>\n                    <jats:p>See related commentary by Green and Neelapu, p. 492.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-19-0813","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T12:55:27Z","timestamp":1580388927000},"page":"552-567","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":288,"title":["Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction"],"prefix":"10.1158","volume":"10","author":[{"given":"Nathan","family":"Singh","sequence":"first","affiliation":[{"name":"1Division of Hematology\/Oncology, University of Pennsylvania Perelman School of Medicine, 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