Venetoclax Resistance Creates Canonical Pyroptosis Vulnerability in AML
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Venetoclax-resistant AML cells, which often adopt monocytic differentiation, retain the canonical pyroptosis machinery of normal monocytes. Across 15 bulk and 4 single-cell cohorts, this pyroptosis program tracked with venetoclax resistance and inferior survival after venetoclax-based therapy; in 24 cell lines and 142 patient specimens, DPP8/9 inhibition by Val-boroPro or NLRP3 activation preferentially killed monocytic AML via GSDMD-mediated pyroptosis. In venetoclax-resistant xenografts, Val-boroPro plus venetoclax reduced leukemia burden and prolonged survival beyond either monotherapy.
Excerpted from biorxiv.org
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- biorxiv.orgPickVenetoclax Resistance Creates Canonical Pyroptosis Vulnerability in AML
Venetoclax-resistant AML cells, which often adopt monocytic differentiation, retain the canonical pyroptosis machinery of normal monocytes. Across 15 bulk and 4 single-cell cohorts, this pyroptosis program tracked with venetoclax resistance and inferior survival after venetoclax-based therapy; in 24 cell lines and 142 patient specimens, DPP8/9 inhibition by Val-boroPro or NLRP3 activation preferentially killed monocytic AML via GSDMD-mediated pyroptosis. In venetoclax-resistant xenografts, Val-boroPro plus venetoclax reduced leukemia burden and prolonged survival beyond either monotherapy.
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