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Acute myeloid leukemia

Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Leukemia volume 33, pages 1373–1386 (2019)Cite this article

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Abstract

Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.

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Acknowledgements

The authors would like to thank the Sequencing and Microarray Core Facility and Flow Cytometry and Cellular Imaging (FCCI) Core Facility which are supported by the MD Anderson Cancer Center Support Grant 5P30 CA016672-40. This project was partially supported by CPRIT RP170295 (CC), the shared Proteomics and Metabolomics core at Baylor College of Medicine with funding from the NIH (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility RP170005 (K Rajapakshe and CC), and the NCI-recognized Dan L. Duncan Cancer Center. CMC acknowledges support from the National Institutes of Health (Grant number R35 CA197589). KNB acknowledges support from the National Institutes of Health (Grant number R01 CA173877). 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: Dyana T. Saenz, Warren Fiskus

Authors and Affiliations

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

    Dyana T. Saenz, Warren Fiskus, Taghi Manshouri, Christopher P. Mill, Prithviraj Bose, Gautam Borthakur, Tapan M. Kadia, Joseph D. Khoury, Lucia Masarova, Agnieszka J. Nowak, Baohua Sun, David N. Saenz, Steven M. Kornblau, Srdan Verstovsek & Kapil N. Bhalla

  2. Arvinas, Inc., 5 Science Park, New Haven, CT, 06511, USA

    Yimin Qian & Kanak Raina

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Kimal Rajapakshe & Cristian Coarfa

  4. β Cat Pharma, 2450 Holcombe Blvd. Suite J606, Houston, TX, 77021, USA

    Raffaella Soldi & Steve Horrigan

  5. Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ, 85004, USA

    Sunil Sharma

  6. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, GA, 30332, USA

    Peng Qiu

  7. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, 06520, USA

    Craig M. Crews

  8. Department of Chemistry, Yale University, New Haven, CT, 06520, USA

    Craig M. Crews

  9. Department of Pharmacology, Yale University, New Haven, CT, 06520, USA

    Craig M. Crews

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  1. Dyana T. Saenz
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Contributions

Conceptualization: KNB. Formal analysis: CC, K Rajapakshe, and PQ. Investigation: DTS, WF, CPM, AJN, BS, and DNS. Resources: YQ, K Raina, CC, K Rajapakshe, TMK, JDK, LM, RS, PB, GB, SMK, SS, SH, CMC. Visualization: DTS, WF, CPM, CC and K Rajapakshe. Writing—original draft: KNB and WF. Writing—review and editing: KNB.

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Correspondence to Kapil N. Bhalla.

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CMC is the founder and Chief Scientific Advisor of, and possesses an equity ownership stake in, Arvinas, Inc. YQ and K Raina are Arvinas employees and possess an equity ownership stake in Arvinas. SH is the founder and Chief Scientific Officer of Beta Cat Pharmaceuticals. The other authors declare that they have no conflict of interest.

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Saenz, D.T., Fiskus, W., Manshouri, T. et al. Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML. Leukemia 33, 1373–1386 (2019). https://doi.org/10.1038/s41375-018-0334-3

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