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

  • Leukemia. 2019 Jun;33(6):1373-1386. doi: 10.1038/s41375-018-0334-3.
Dyana T Saenz   #  1 ,  Warren Fiskus   #  1 ,  Taghi Manshouri  1 ,  Christopher P Mill  1 ,  Yimin Qian  2 ,  Kanak Raina  2 ,  Kimal Rajapakshe  3 ,  Cristian Coarfa  3 ,  Raffaella Soldi  4 ,  Prithviraj Bose  1 ,  Gautam Borthakur  1 ,  Tapan M Kadia  1 ,  Joseph D Khoury  1 ,  Lucia Masarova  1 ,  Agnieszka J Nowak  1 ,  Baohua Sun  1 ,  David N Saenz  1 ,  Steven M Kornblau  1 ,  Steve Horrigan  4 ,  Sunil Sharma  5 ,  Peng Qiu  6 ,  Craig M Crews  7  8  9 ,  Srdan Verstovsek  1 ,  Kapil N Bhalla  10
Affiliations
  • 1. The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2. Arvinas, Inc., 5 Science Park, New Haven, CT, 06511, USA.
  • 3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 4. β Cat Pharma, 2450 Holcombe Blvd. Suite J606, Houston, TX, 77021, USA.
  • 5. Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ, 85004, USA.
  • 6. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, GA, 30332, USA.
  • 7. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, 06520, USA.
  • 8. Department of Chemistry, Yale University, New Haven, CT, 06520, USA.
  • 9. Department of Pharmacology, Yale University, New Haven, CT, 06520, USA.
  • 10. The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • # Contributed equally.
PMID: 30575820 DOI: 10.1038/s41375-018-0334-3
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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