Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells
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Hanyang Lin1,2, Min Chen1, Katharina Rothe1,3, Matthew V. Lorenzi4, Adrian Woolfson4 and Xiaoyan Jiang1,2,3
1 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada
2 Department of Medicine, University of British Columbia, Vancouver, BC, Canada
3 Department of Medical Genetics, University of British Columbia; Vancouver, BC, Canada
4 Discovery Medicine Oncology, Bristol-Myers Squibb, Princeton, NJ, United States
Xiaoyan Jiang, email:
Keywords: CML, BCR-ABL, leukemic stem cells, JAK2, TKI resistance, BMS-911543
Received: August 13, 2014 Accepted: August 15, 2014 Published: August 16, 2014
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.
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