Mechanistic basis and efficacy of targeting the β-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors.

ABSTRACT: The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the β-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, po

SUBMITTER: Saenz DT 

PROVIDER: S-EPMC7146021 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature