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

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.

• Authors: Dyana T Saenz, Warren Fiskus, Taghi Manshouri, Christopher P Mill, Yimin Qian, Kanak Raina, Kimal Rajapakshe, Cristian Coarfa, Raffaella Soldi, Prithviraj Bose, Gautam Borthakur, Tapan M Kadia, Joseph D Khoury, Lucia Masarova, Agnieszka J Nowak, Baohua Sun, David N Saenz, Steven M Kornblau, Steve Horrigan, Sunil Sharma, Peng Qiu, Craig M Crews, Srdan Verstovsek, Kapil N Bhalla
• Journal: Leukemia (Leukemia) Vol. 33 Issue 6 Pg. 1373-1386 (06 2019) ISSN: 1476-5551 [Electronic] England
• PMID: 30575820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetanilides
• Heterocyclic Compounds, 3-Ring
• Nitriles
• OTX015
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• beta Catenin
• ruxolitinib

Topics

• Acetanilides (pharmacology)
• Animals
• Apoptosis (drug effects)
• CRISPR-Cas Systems
• Cell Nucleus (drug effects, metabolism, pathology)
• Drug Synergism
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (complications, drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Myeloproliferative Disorders (complications, drug therapy, metabolism, pathology)
• Nitriles
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines
• Signal Transduction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• beta Catenin (antagonists & inhibitors, genetics, metabolism)