2. Academic Validation
  3. Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

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

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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