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ACUTE MYELOID LEUKEMIA

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

Leukemia volume 38, pages 545–556 (2024)Cite this article

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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.

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Fig. 1: Treatment with BET inhibitor OTX015 or β-catenin antagonist TV depletes EVI1 and c-Myc expression and dose-dependently induces lethality in 3q26.2-rearranged EVI1-expressing AML cells.
Fig. 2: Treatment with TV blocks TBL1 co-localization with key transcription factors β-catenin, LEF1 and EVI1.
Fig. 3: Treatment with TV reduces H3K27Ac occupancy on super-enhancer-driven genes, the MECOM locus and affects chromatin looping of the MYC super-enhancer with its promoter in 3q26.2-rearranged AML cells.
Fig. 4: Treatment with TV-induced inflammatory response and apoptosis gene-sets with concomitant depletion of MYC target gene-sets and EVI1 target genes in 3q26.2-rearranged AML cells.
Fig. 5: TV treatment depletes EVI1 and MYC levels in phenotypically defined leukemia stem cells.
Fig. 6: Co-treatment with TV and OTX015 or venetoclax exerts synergistic lethal activity against 3q26.2-rearranged AML cells.
Fig. 7: Compared to single agent treatment, co-treatment with TV and OTX015 or venetoclax exerts superior anti-leukemia activity and improves survival of mice bearing 3q26.2-rearranged AML xenografts.

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Data availability

The datasets generated during and/or analyzed during the current study are available in the GEO repository as a Super Series and have been assigned Accession ID: GSE247095.

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Acknowledgements

The authors would like to thank the Advanced Technology Genomics Core (ATGC), Flow Cytometry and Cellular Imaging (FCCI) Core Facility, which are supported by the MD Anderson Cancer Center Support Grant 5P30 CA016672-40. NextGen sequencing studies performed utilizing the NovaSeq6000 were supported by a grant from the NIH (1S10OD024977-01). KNB was supported by a grant from the NIH (R01 CA255721). This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632).

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Author notes

  1. These authors contributed equally: Christine E. Birdwell, Warren Fiskus.

Authors and Affiliations

  1. M.D. Anderson Cancer Center, The University of Texas, Houston, TX, 77030, USA

    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, Xinjia Ruan, Xiaoping Su, Hagop Kantarjian & Kapil N. Bhalla

  2. TGen, Phoenix, AZ, 85004, USA

    Sunil Sharma

  3. Iterion Therapeutics, Houston, TX, 77021, USA

    Stephen Horrigan

  4. University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Joseph D. Khoury

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Contributions

KNB designed the study, analyzed data, and wrote the manuscript. XR and XS performed bioinformatics analyses. CB, WF, CPM, JAD, KD and JDK performed research and analyzed the data. TMK, KS, ND, CDD, NP, GB, SS, SH and HK contributed critical reagents. WF also wrote the manuscript.

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Correspondence to Kapil N. Bhalla.

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SH is the Chief Scientific Officer at Iterion Therapeutics. KNB has served as a consultant to Iterion Therapeutics. All other authors declare they have no conflict of interest to disclose.

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Birdwell, C.E., Fiskus, W., Kadia, T.M. et al. Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression. Leukemia 38, 545–556 (2024). https://doi.org/10.1038/s41375-023-02108-3

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