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

Hanyang Lin,Katharina Rothe,Xiaoyan Jiang,Matthew V Lorenzi,Min Chen,Adrian Woolfson

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.

Highlights

Chronic myeloid leukemia (CML) is a lethal hematological malignancy defined by the presence of a BCR-ABL fusion gene originating in a hematopoietic stem cell (HSC) [1, 2]
These results indicate that the combination of BMS-911543 and Imatinib Mesylate (IM) result in a deeper suppression of p-STAT5 and more effectively reduce the proliferative capacity of IM-resistant cells than either single agent alone
While BMS-911543 (300 nM) had minimal effects on apoptosis and single tyrosine kinase inhibitor (TKI) (5 μM IM; 150 nM DA; 5 μM NL) increased the percentage of Annexin V positive cells by 10-20%, the combination treatment increased Annexin V positive cells to 20-30% at 48 hours, with www.impactjournals.com/oncotarget a significant increase as a result of the combination treatment after 72 hours (2-fold, P

Summary

Introduction

Chronic myeloid leukemia (CML) is a lethal hematological malignancy defined by the presence of a BCR-ABL fusion gene originating in a hematopoietic stem cell (HSC) [1, 2]. Despite the effectiveness of TKI monotherapy, most patients harbor residual leukemic stem cells (LSCs), and disease typically recurs if therapy is discontinued [12, 13]. 15-20% of patients with early CPCML and up to 40% with accelerated phase (AP-CML) disease fail treatment, indicating a need for alternative approaches. Recent studies have indicated that CML LSCs might not be exclusively dependent on BCR-ABL TK activity for their survival [18, 19]. These observations emphasize the need to develop new therapeutic agents and combination www.impactjournals.com/oncotarget strategies to target TKI resistant LSC subclones.

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Results

Conclusion