title: Role of Growth arrest-specific gene 6-Mer axis in multiple myeloma.
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.
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Waizenegger
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Ben-Batalla
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Meissner
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wroblewski
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Janning
authors.affiliation: Department of Stem Cell Transplantation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Riecken
authors.affiliation: Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Binder
authors.affiliation: Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Atanackovic
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Taipaleenmaeki
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schewe
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sawall
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Gensch
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Cubas-Cordova
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Seckinger
authors.affiliation: Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Hesse
authors.affiliation: Department of Stem Cell Transplantation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Department of Stem Cell Transplantation, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Fehse
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.affiliation: Institute of Research in Biotherapy, University Hospital of Montpellier (CHU), Montpellier, France.
authors.forename: B
authors.initials: B
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Raab
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: 1] Department of Hematology and Oncology, BMT with Section of Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Loges
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009368:Neoplasm Transplantation; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014859:Warfarin / Q000494:pharmacology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D014859:Warfarin; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C097072:MERTK protein, human; C084944:TYRO3 protein, human
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