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We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell\u2013specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically.<\/jats:p>","DOI":"10.1083\/jcb.202212074","type":"journal-article","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T02:21:38Z","timestamp":1699582898000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Phosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma"],"prefix":"10.1083","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-6045","authenticated-orcid":true,"given":"Jumpei","family":"Omi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/057zh3y96","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo 1 Department of Health Chemistry, , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5478-809X","authenticated-orcid":true,"given":"Taiga","family":"Kato","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027y26122","id-type":"ROR","asserted-by":"publisher"}],"name":"Daiichi Sankyo Co., Ltd. 2 , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7634-8519","authenticated-orcid":true,"given":"Yohei","family":"Yoshihama","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027y26122","id-type":"ROR","asserted-by":"publisher"}],"name":"Daiichi Sankyo Co., Ltd. 2 , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-1933","authenticated-orcid":true,"given":"Koki","family":"Sawada","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/057zh3y96","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo 1 Department of Health Chemistry, , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0871-8477","authenticated-orcid":true,"given":"Nozomu","family":"Kono","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/057zh3y96","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo 1 Department of Health Chemistry, , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9435-1896","authenticated-orcid":true,"given":"Junken","family":"Aoki","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/057zh3y96","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo 1 Department of Health Chemistry, , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,12,4]]},"reference":[{"key":"2023120416301958000_bib1","doi-asserted-by":"publisher","first-page":"12888","DOI":"10.1074\/jbc.M800714200","article-title":"Defining the importance of phosphatidylserine synthase-1 (PSS1): Unexpected viability of PSS1-deficient mice","volume":"283","author":"Arikketh","year":"2008","journal-title":"J. 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