Preclinical Efficacy of Targeting Epigenetic Mechanisms in Aml With 3q26 Lesions and EVI1 Overexpression

Authors

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

Language

English

Publication Date

3-1-2024

Journal

Leukemia

DOI

10.1038/s41375-023-02108-3

PMID

38086946

PMCID

PMC12122007

PubMedCentral® Posted Date

5-29-2026

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Animals, Mice, Transcription Factors, MDS1 and EVI1 Complex Locus Protein, Nuclear Proteins, Antineoplastic Agents, Leukemia, Myeloid, Acute, Epigenesis, Genetic, Proto-Oncogenes, Bromodomain Containing Proteins, Cell Cycle Proteins, EVI1, MECOM, Epigenetics, tegavivint, BET inhibitor, HAT inhibitor, venetoclax

Published Open-Access

yes

Recommended Citation

Birdwell, Christine E; Fiskus, Warren; Kadia, Tapan M; et al., "Preclinical Efficacy of Targeting Epigenetic Mechanisms in Aml With 3q26 Lesions and EVI1 Overexpression" (2024). Faculty, Staff and Student Publications. 5565.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5565