{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:39:17Z","timestamp":1792931957257,"version":"4.5.0"},"reference-count":135,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA\/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS\/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid\/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody\u2013drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cancers17091586","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T04:20:26Z","timestamp":1746591626000},"page":"1586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Unraveling Venetoclax Resistance: Navigating the Future of HMA\/Venetoclax-Refractory AML in the Molecular Era"],"prefix":"10.3390","volume":"17","author":[{"given":"Theodora","family":"Chatzilygeroudi","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine and Research Unit, Hematology Unit, National and Kapodistrian University of Athens School of Medicine, Attikon University Hospital, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-8298","authenticated-orcid":false,"given":"Theodoros","family":"Karantanos","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Pappa","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine and Research Unit, Hematology Unit, National and Kapodistrian University of Athens School of Medicine, Attikon University Hospital, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1158\/2159-8290.CD-16-0313","article-title":"Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia","volume":"6","author":"Konopleva","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. 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