{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:00:46Z","timestamp":1792612846503,"version":"4.5.0"},"reference-count":30,"publisher":"American Society of Hematology","issue":"8","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed\/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (\u22651 of neutropenia, thrombocytopenia, anemia) lasting \u22654 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13\/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.<\/jats:p>","DOI":"10.1182\/blood.2021012775","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T20:18:31Z","timestamp":1630527511000},"page":"1198-1207","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":86,"title":["Clonal hematopoiesis, myeloid disorders and <i>BAX<\/i>-mutated myelopoiesis in patients receiving venetoclax for CLL"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-0022","authenticated-orcid":false,"given":"Piers","family":"Blombery","sequence":"first","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-2432","authenticated-orcid":false,"given":"Thomas E.","family":"Lew","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1693-1761","authenticated-orcid":false,"given":"Michael A.","family":"Dengler","sequence":"additional","affiliation":[{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;"},{"name":"Division on Oncology, Medical University of Graz, Graz, Austria; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5206-5111","authenticated-orcid":false,"given":"Ella R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3432-0785","authenticated-orcid":false,"given":"Victor S.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamia","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Panigrahi","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8790-4675","authenticated-orcid":false,"given":"Sasanka M.","family":"Handunnetti","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3239-6065","authenticated-orcid":false,"given":"Dennis A.","family":"Carney","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"University of Melbourne, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Westerman","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-5017","authenticated-orcid":false,"given":"Constantine S.","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia;"},{"name":"University of Melbourne, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry M.","family":"Adams","sequence":"additional","affiliation":[{"name":"University of Melbourne, Melbourne, VIC, Australia;"},{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Wei","sequence":"additional","affiliation":[{"name":"The Alfred Hospital and Monash University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-4873","authenticated-orcid":false,"given":"David C. 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