Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Case-Control Studies
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred NOD
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Multiple Myeloma / genetics*
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Multiple Myeloma / mortality
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Multiple Myeloma / pathology
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Multiple Myeloma / therapy
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Neoplasm Transplantation
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Plasma Cells / metabolism*
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Plasma Cells / pathology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism
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Signal Transduction
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Stromal Cells / metabolism
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Stromal Cells / pathology
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Survival Analysis
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Warfarin / pharmacology
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c-Mer Tyrosine Kinase
Substances
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Intercellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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growth arrest-specific protein 6
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Warfarin
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MERTK protein, human
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Receptor Protein-Tyrosine Kinases
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TYRO3 protein, human
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c-Mer Tyrosine Kinase
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Axl Receptor Tyrosine Kinase