{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:40:20Z","timestamp":1792608020740,"version":"4.5.0"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,22]]},"abstract":"<jats:p>Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in patients with acute myeloid leukemia (AML). Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56\u03b1 enhances the proapoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics\u2013based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56\u03b1 complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56\u03b1 heterocomplex with the potentially novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza\u2013sensitive and \u2013resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56\u03b1 stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.<\/jats:p>","DOI":"10.1172\/jci.insight.205218","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:01:26Z","timestamp":1789488086000},"source":"Crossref","is-referenced-by-count":0,"title":["Stabilization of the PP2A-B56\u03b1 complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML"],"prefix":"10.1172","volume":"11","author":[{"given":"Silvia","family":"Romero-Murillo","sequence":"first","affiliation":[{"name":"Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Navarra, Spain."},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra, Pamplona, Spain."},{"name":"Centro de Investigaci\u00f3n M\u00e9dica Aplicada 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