TY - JOUR
T1 - Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression
AU - Birdwell, Christine E.
AU - Fiskus, Warren
AU - Kadia, Tapan M.
AU - Mill, Christopher P.
AU - Sasaki, Koji
AU - Daver, Naval
AU - DiNardo, Courtney D.
AU - Pemmaraju, Naveen
AU - Borthakur, Gautam
AU - Davis, John A.
AU - Das, Kaberi
AU - Sharma, Sunil
AU - Horrigan, Stephen
AU - Ruan, Xinjia
AU - Su, Xiaoping
AU - Khoury, Joseph D.
AU - Kantarjian, Hagop
AU - Bhalla, Kapil N.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2023.
PY - 2024/3
Y1 - 2024/3
N2 - AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
AB - AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
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U2 - 10.1038/s41375-023-02108-3
DO - 10.1038/s41375-023-02108-3
M3 - Article
C2 - 38086946
AN - SCOPUS:85179362065
SN - 0887-6924
VL - 38
SP - 545
EP - 556
JO - Leukemia
JF - Leukemia
IS - 3
ER -