title: Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells.
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.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hanyang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. Department of Medical Genetics, University of British Columbia; Vancouver, BC, Canada.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rothe
authors.affiliation: Discovery Medicine Oncology, Bristol-Myers Squibb, Princeton, NJ, United States.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Lorenzi
authors.affiliation: Discovery Medicine Oncology, Bristol-Myers Squibb, Princeton, NJ, United States.
authors.forename: Adrian
authors.initials: A
authors.lastname: Woolfson
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada. Department of Medicine, University of British Columbia, Vancouver, BC, Canada. Department of Medical Genetics, University of British Columbia; Vancouver, BC, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D001549:Benzamides; C082869:CRKL protein; D006575:Heterocyclic Compounds, 3-Ring; C571029: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; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; D000068877:Imatinib Mesylate; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D016315:Proto-Oncogene Proteins c-abl; D000069439:Dasatinib