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Myeloma

PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma

Leukemia volume 27, pages 702–710 (2013)Cite this article

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Abstract

Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients’ bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages’ ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.

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Acknowledgements

This work was supported by National Cancer Institute grants R01 CA138402, R01 CA138398, R01 CA163881, and P50 CA142509; Leukemia & Lymphoma Society translational research grants; the Multiple Myeloma Research Foundation, the Commonwealth Foundation for Cancer Research; the Center for Targeted Therapy of The University of Texas MD. Anderson Cancer Center; and a grant for International Cooperation of the National Natural Science Foundation of China (81120108018). We thank our departmental Myeloma Tissue Bank for providing patients’ samples.

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Authors and Affiliations

  1. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Zheng, J Yang, J Qian, Y Lu, Z Wang, Z Liu, H Li, J He, D Weber, R E Davis, L Kwak & Q Yi

  2. Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Qiu

  3. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Hanabuchi

  4. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Lin

  5. Department of Hematology, Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Z Cai

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Correspondence to Q Yi.

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Zheng, Y., Yang, J., Qian, J. et al. PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 27, 702–710 (2013). https://doi.org/10.1038/leu.2012.272

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