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With recent approval of the anti\u2010CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells.<jats:italic>In vitro<\/jats:italic>Dara treatment of WM cells (including ibrutinib\u2010resistant lines) elicited antibody\u2010dependent cellular cytotoxicity (ADCC), complement\u2010dependent cytotoxicity (CDC), antibody\u2010dependent cell phagocytosis (ADCP) and direct apoptosis.<jats:italic>In vivo<\/jats:italic>, Dara treatment was well tolerated and delayed tumour growth in RPCI\u2010WM1\u2010xenografted mice. CD38 is reported to augment B\u2010cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLC\u03b32, ERK1\/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib\u2010resistant WM cell lines treated with the ibrutinib\u00a0+\u00a0Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single\u2010agent Dara or ibrutinib. In summary, we are the first to report the<jats:italic>in\u00a0vitro<\/jats:italic>and<jats:italic>in\u00a0vivo<\/jats:italic>anti\u2010WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co\u2010targeted with ibrutinib\u00a0+\u00a0Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.<\/jats:p>","DOI":"10.1111\/bjh.15515","type":"journal-article","created":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T10:05:14Z","timestamp":1533636314000},"page":"196-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Targeting CD38 with daratumumab is lethal to Waldenstr\u00f6m macroglobulinaemia cells"],"prefix":"10.1111","volume":"183","author":[{"given":"Aneel","family":"Paulus","sequence":"first","affiliation":[{"name":"Department of Cancer Biology Mayo Clinic Jacksonville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alak","family":"Manna","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology Mayo Clinic Jacksonville FL 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