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Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin\u2013really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane\u2013associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective \u03b3-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.<\/jats:p>","DOI":"10.1182\/blood.2022018752","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T18:54:07Z","timestamp":1685127247000},"page":"973-988","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":27,"title":["DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance"],"prefix":"10.1182","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9524-4275","authenticated-orcid":false,"given":"Nan","family":"Zhou","sequence":"first","affiliation":[{"name":"1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 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