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• W4378573946 abstract "Abstract Uncontrolled proliferation and apoptosis evasion are two hallmarks of acute myeloid leukemia (AML), but the molecular mechanisms remain poorly understood. In this study, it is demonstrated that the double over‐expresser of oncoprotein c‐Myc and anti‐apoptotic protein Bcl‐2 is a critical “genetic overdrive” of proliferation and apoptosis evasion in AML and is associated with poor genetic alterations. Double‐knockdown of c‐Myc/ Bcl‐2 synergistically kills AML cells in vitro and in vivo. Moreover, a novel oral small molecule combination co‐targeting c‐Myc and Bcl‐2 with WBC100 and Venetoclax (VEN) at low doses are developed. Importantly, the study shows that this combination results in deep and durable remissions of AML, and its efficacy is superior to the frontline combination of Venetoclax and hypomethylation azacitidine (AZA) in AML mouse models and PDX models from relapsed or refractory AML patients. Mechanically, Bcl‐2 knockdown induces mitochondrial outer membrane permeabilization and c‐Myc‐knockdown impairs mitochondria biogenesis. Co‐targeting c‐Myc/Bcl‐2 reciprocally abrogates over‐proliferation and apoptosis resistance via forming a double hit to mitochondrial biogenesis and apoptosis machinery. The findings for the first time demonstrate that co‐targeting c‐Myc/Bcl‐2 by the novel oral small molecule combination of WBC100/Venetoclax is a promising and convenient therapy for AML and support its clinical trial." @default.
• W4378573946 created "2023-05-28" @default.
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• W4378573946 date "2023-06-08" @default.
• W4378573946 modified "2023-10-17" @default.
• W4378573946 title "Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models" @default.
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• W4378573946 doi "https://doi.org/10.1002/adtp.202300013" @default.
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