Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells

Oncotarget. 2014 Sep 30;5(18):8637-50. doi: 10.18632/oncotarget.2353.

Abstract

Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IM-resistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34+ treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigens, CD34 / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / administration & dosage
  • Cell Proliferation / drug effects
  • Dasatinib
  • Drug Resistance, Neoplasm*
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Humans
  • Imatinib Mesylate
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology
  • Nuclear Proteins / metabolism
  • Piperazines / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / administration & dosage
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Thiazoles / administration & dosage
  • Time Factors
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD34
  • Benzamides
  • CRKL protein
  • Heterocyclic Compounds, 3-Ring
  • N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide
  • Nuclear Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • STAT5 Transcription Factor
  • Thiazoles
  • Imatinib Mesylate
  • JAK2 protein, human
  • Janus Kinase 2
  • Proto-Oncogene Proteins c-abl
  • Dasatinib