{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:11:38Z","timestamp":1792087898498,"version":"4.4.0"},"reference-count":121,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Overexpression of the anti-apoptotic protein BCL-2 is a key factor in the pathogenesis of chronic lymphocytic leukemia (CLL) and is associated with poor clinical outcomes. Therapeutic activation of apoptosis in cancer cells using the BCL-2 inhibitor (BCL2i) venetoclax has shown remarkable efficacy in clinical trials, both as monotherapy and combination regimens. However, patients with CLL experience a highly variable clinical course, facing significant challenges in advanced stages due to disease relapse and the emergence of resistant clones. Resistance mechanisms include acquired BCL-2 mutations, alteration of pro-apoptotic and anti-apoptotic proteins, metabolic reprogramming, epigenetic changes, and aberrant signaling pathways. To address this complex disease and improve progression-free survival, strategies targeting multiple signaling pathways and mechanisms have been explored. Randomized clinical trials of venetoclax in combination with Bruton tyrosine kinase (BTK) inhibitors or CD20 monoclonal antibodies have significantly outperformed traditional chemoimmunotherapy in both treatment-na\u00efve and relapsed patients, achieving undetectable minimal residual disease (uMRD) and durable remissions. This review explores the intricate balance between BCL-2 family proteins and their role in the intrinsic apoptosis pathway, discusses venetoclax resistance mechanisms, and highlights the evolving role of venetoclax and other BCL2i-based combination therapies in CLL treatment.<\/jats:p>","DOI":"10.3390\/cells13221922","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T03:57:04Z","timestamp":1732075024000},"page":"1922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BCL2i-Based Therapies and Emerging Resistance in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"13","author":[{"given":"Wing Fai","family":"Li","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Jacobi Medical Center, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Atalla","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, The University of Texas at San Antonio, San Antonio, TX 78249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9347-2212","authenticated-orcid":false,"given":"Marina","family":"Konopleva","sequence":"additional","affiliation":[{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/382545a0","article-title":"Transcriptional Regulator of Programmed Cell Death Encoded by Caenorhabditis Elegans Gene Ces-2","volume":"382","author":"Metzstein","year":"1996","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1182\/asheducation-2005.1.278","article-title":"CLL Biology and Prognosis","volume":"2005","author":"Dighiero","year":"2005","journal-title":"Hematology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1182\/blood-2005-06-2508","article-title":"Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992\u20132001","volume":"107","author":"Morton","year":"2006","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrc2764","article-title":"From Pathogenesis to Treatment of Chronic Lymphocytic Leukaemia","volume":"10","author":"Zenz","year":"2010","journal-title":"Nat. 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