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. Epub 2018 Dec 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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