Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer+ BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy.
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SL is supported by the Max-Eder group leader program from Deutsche Krebshilfe, the Deutsche Forschungsgemeinschaft (DFG), the Roggenbuck Stiftung, the Hamburger Krebsgesellschaft, the Medical Faculty of the University of Hamburg (FFM program) and the Hamburger Exzellenzinitiative (LEXI program). HT was supported by an EMBO Long Term Postdoctoral Fellowship and by a Post-Doctoral fellowship from the Alexander von Humboldt foundation. EH is supported by the DFG Heisenberg-Program and receives funding from DFG. MJ is supported by a Hubertus-Wald fellowship. KP is supported by the ERC Advanced Investigator Grant no. 269081 “DISSECT”. We thank Dr. Carol Stocking (Heinrich Pette Institute, Hamburg, Germany) for supplying OP9 cells. We thank Nils Jäger on behalf of the Animal Facility (VTH) at University Medical Center Hamburg-Eppendorf for taking care of the mice housing and the FACS core facility of the UKE for the sorting.
SL initiated, conceived of, designed and supervised research, wrote the manuscript and analyzed data. JSW and IBB designed experiments, wrote the manuscript, performed experiments and analyzed data. NW, TM, MW, KR, HT, SS, VG, MCC and MJ performed experiments and data analysis. MB, DA, DS, WF, EH, NK, BF, DH, BK, MSR, KP and CB contributed vital new reagents and commented on the research direction and edited the manuscript. All authors discussed and commented on the manuscript.
The authors declare no conflict of interest.
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Waizenegger, J., Ben-Batalla, I., Weinhold, N. et al. Role of Growth arrest-specific gene 6-Mer axis in multiple myeloma. Leukemia 29, 696–704 (2015) doi:10.1038/leu.2014.236
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