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We generated mice that express a human lymphoma\u2013derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus\u2013like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL\u2013RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell\u2013intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.<\/jats:p>","DOI":"10.1084\/jem.20200517","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T13:17:21Z","timestamp":1602681441000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5073-8300","authenticated-orcid":true,"given":"Beg\u00fcm","family":"Alankus","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany 1"},{"name":"TranslaTUM, Center for 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