{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:01:32Z","timestamp":1780081292000,"version":"3.54.0"},"reference-count":22,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Polatuzumab vedotin, an antibody\u2010drug conjugate (ADC) targeting the B cell receptor (BCR) signaling subunit CD79B, has recently entered frontline therapy for diffuse large B cell lymphoma (DLBCL) and high\u2010grade B cell lymphoma (HGBCL), achieving encouraging clinical results. However, MYC\u2010driven B cell lymphomas, particularly HGBCL with\n                    <jats:italic>MYC<\/jats:italic>\n                    and\n                    <jats:italic>BCL2<\/jats:italic>\n                    rearrangements, frequently silence surface BCR\/CD79B expression, limiting the therapeutic reach of CD79B\u2010directed ADCs and underscoring the need for complementary treatment strategies. To uncover drug vulnerabilities associated with BCR extinction in aggressive B cell lymphomas, we conditionally ablated surface BCR expression in the\n                    <jats:italic>\u03bb<\/jats:italic>\n                    \u2010MYC mouse B cell lymphoma model and screened 1475 small\u2010molecule compounds, including clinically approved agents, on syngenic BCR\u2010positive and BCR\u2010negative tumor cells. This screening revealed compounds with comparable activity across both states as well as compounds with improved efficacy against BCR\u2010deficient lymphomas. Notably, inhibitors of mTORC1\/2 and CDK4\/6 displayed robust and reproducible potency in BCR\u2010negative lymphoma cells. Mechanistically, BCR loss impaired mTOR\u2010dependent anabolic control, reducing protein synthesis, while diminished Cyclin D3 abundance sensitized tumor cells to pharmacological CDK4\/6 blockade. Human BCR\u2010negative HGBCL with\n                    <jats:italic>MYC<\/jats:italic>\n                    and\n                    <jats:italic>BCL2<\/jats:italic>\n                    rearrangements similarly exhibited sub\u2010micromolar sensitivity to mTORC1\/2 and CDK4\/6 inhibitors. Overall, our results uncover targetable vulnerabilities in MYC\u2010driven B cell lymphomas, possibly extending to other aggressive B cell tumors silencing BCR expression. The data provide a rational basis for integrating CD79B\u2010directed ADCs with mTOR or CDK4\/6 inhibitors to prevent or overcome treatment resistance of aggressive B cell lymphomas.\n                  <\/jats:p>","DOI":"10.1002\/hon.70175","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T08:50:20Z","timestamp":1770799820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targetable Vulnerabilities in MYC\u2010Driven B Cell Lymphomas Resistant to BCR Extinction"],"prefix":"10.1002","volume":"44","author":[{"given":"Silvia","family":"Brambillasca","sequence":"first","affiliation":[{"name":"Experimental Therapeutics Program IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicara Chantal","family":"Parr","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Palmeri","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Andronache","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Program IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Arima","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7674-2583","authenticated-orcid":false,"given":"Giovanni","family":"Faga\u2019","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Program IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Program IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Perucho","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Robusto","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Program IFOM 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Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Varano","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciro","family":"Mercurio","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Program IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Casola","sequence":"additional","affiliation":[{"name":"Genetics of B Cells and Lymphoma Unit IFOM ETS\u2010The AIRC Institute of Molecular Oncology  Milano Italy"},{"name":"Department of Medical Biotechnology and Translational Medicine University of Milano  Milano 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