Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression

Christine E. Birdwell, Warren Fiskus, Tapan M. Kadia, Christopher P. Mill, Koji Sasaki, Naval Daver, Courtney D. DiNardo, Naveen Pemmaraju, Gautam Borthakur, John A. Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D. Khoury, Hagop Kantarjian, Kapil N. Bhalla

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)545-556
Number of pages12
JournalLeukemia
Volume38
Issue number3
DOIs
StatePublished - Mar 2024

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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