Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML
| Autor: | Srdan Verstovsek, Steve Horrigan, Christopher P. Mill, Sunil Sharma, Steven M. Kornblau, Craig M. Crews, Taghi Manshouri, Baohua Sun, Kapil N. Bhalla, Prithviraj Bose, Agnieszka J Nowak, Tapan M. Kadia, Peng Qiu, Kimal Rajapakshe, Raffaella Soldi, David N. Saenz, Gautam Borthakur, Warren Fiskus, Dyana T. Saenz, Kanak Raina, Cristian Coarfa, Lucia Masarova, Joseph D. Khoury, Yimin Qian |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Ruxolitinib Myeloid Apoptosis Mice SCID 03 medical and health sciences Mice 0302 clinical medicine Mice Inbred NOD Survivin Nitriles medicine Tumor Cells Cultured Animals Humans Progenitor cell Protein Kinase Inhibitors Myeloproliferative neoplasm beta Catenin Cell Nucleus Gene knockdown Myeloproliferative Disorders business.industry food and beverages Drug Synergism Hematology medicine.disease Xenograft Model Antitumor Assays Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Pyrimidines Oncology 030220 oncology & carcinogenesis Cancer research Pyrazoles Acetanilides CRISPR-Cas Systems business Heterocyclic Compounds 3-Ring medicine.drug Signal Transduction |
| Zdroj: | Leukemia. 33(6) |
| ISSN: | 1476-5551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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