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High IL-7 levels in the bone marrow microenvironment mediate imatinib resistance and predict disease progression in chronic myeloid leukemia

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Abstract

Chronic myeloid leukemia (CML) is a three-stage myeloproliferative disease caused by translocation between chromosomes 9 and 22. Although tyrosine kinase inhibitors (TKI) are highly effective in the treatment of CML, numerous clinical trials have shown that many patients become refractory or drug resistance, especially those in the blastic crisis of CML. The molecular mechanisms underlying CML, however, remain poorly understood. In the present study, we used a coculture model to address possible mechanisms underlying the involvement of bone marrow microenvironment in the drug resistance of CML. Our data show that interleukin-7(IL-7) levels in the bone marrow of CML patients in blastic crisis are significantly higher than those of both healthy persons and CML patients in chronic and accelerated phases. The increased IL-7 was secreted by mesenchymal stem cells (MSC) in the bone marrow, which may protect leukemic cells from apoptosis induced by imatinib through JAK1/STAT5 signaling pathway. Our findings suggest that therapeutic strategies IL-7 signaling pathway may represent a promising approach for improving CML therapy, especially for patients in blastic crisis.

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Acknowledgments

We would like to thank the staff of the Jiangxi Key Laboratory of Molecular Medicine for their technical support and those of Department of Hematology, the Second Affiliated Hospital of Nanchang University for the collection of specimens. This study is supported by Grants from National Natural Science Foundation of China (81260231), Major Basic Research Projects of Jiangxi Province (20143ABC20005), Jiangxi Provincial Health and Family Planning Commission Science and Technology Program (20155645), Graduate Student Innovation Fund of Jiangxi Province (YC2014-B023).

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    Authors and Affiliations

    1. The Key Laboratory of Hematology of Jiangxi Province, The Department of Hematology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, P.R. China

      Xiaoyan Zhang, Yazhi Yang, Qian Wan, Lijun Fang, Qiong Wu & Jian Li

    2. Basic Medical school, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China

      Xiaoyan Zhang

    3. The Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, P.R. China

      Huaijun Tu

    4. Graduate School of Medicine, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China

      Xiaoyan Zhang, Yazhi Yang, Qian Wan & Lijun Fang

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    1. Xiaoyan Zhang
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    Correspondence to Jian Li.

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    X. Zhang and H. Tu contribute equally to this study and share first authorship.

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    Zhang, X., Tu, H., Yang, Y. et al. High IL-7 levels in the bone marrow microenvironment mediate imatinib resistance and predict disease progression in chronic myeloid leukemia. Int J Hematol 104, 358–367 (2016). https://doi.org/10.1007/s12185-016-2028-9

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    • DOI: https://doi.org/10.1007/s12185-016-2028-9

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