A niche-dependent myeloid transcriptome signature defines dormant myeloma cells.

Autor:	Khoo WH; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia., Ledergor G; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.; Department of Internal Medicine 'T', Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Weiner A; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel., Roden DL; Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia., Terry RL; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., McDonald MM; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Chai RC; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., De Veirman K; Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium., Owen KL; Department of Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia., Opperman KS; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Vandyke K; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Clark JR; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Seckinger A; Labor für Myelomforschung, Medizinische Klinik V, Universitätsklinikum Heidelberg, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany., Kovacic N; Department of Anatomy and Clinical Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia., Nguyen A; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.; Immunology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia., Mohanty ST; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., Pettitt JA; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., Xiao Y; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., Corr AP; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Seeliger C; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia., Novotny M; J. Craig Venter Institute, La Jolla, CA., Lasken RS; J. Craig Venter Institute, La Jolla, CA., Nguyen TV; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.; School of Biomedical Engineering, University of Technology, Sydney, NSW, Australia., Oyajobi BO; Department of Cell Systems and Anatomy, Long School of Medicine, and.; Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX; and., Aftab D; Exelixis Inc, Alameda, CA., Swarbrick A; Cancer Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Parker B; Department of Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia., Hewett DR; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Hose D; Labor für Myelomforschung, Medizinische Klinik V, Universitätsklinikum Heidelberg, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany., Vanderkerken K; Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium., Zannettino ACW; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Amit I; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel., Phan TG; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.; Immunology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia., Croucher PI; Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.; School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2019 Jul 04; Vol. 134 (1), pp. 30-43. Date of Electronic Publication: 2019 Apr 25.
DOI:	10.1182/blood.2018880930
Abstrakt:	The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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