Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/120452
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Type: Journal article
Title: A niche-dependent myeloid transcriptome signature defines dormant myeloma cells
Author: Khoo, W.
Ledergor, G.
Weiner, A.
Roden, D.
Terry, R.
McDonald, M.
Chai, R.
De Veirman, K.
Owen, K.
Opperman, K.
Vandyke, K.
Clark, J.
Seckinger, A.
Kovacic, N.
Nguyen, A.
Mohanty, S.
Pettitt, J.
Xiao, Y.
Corr, A.
Seeliger, C.
et al.
Citation: Blood, 2019; 134(1):30-43
Publisher: American Society of Hematology
Issue Date: 2019
ISSN: 0006-4971
1528-0020
Statement of
Responsibility: 
Weng Hua Khoo … Khatora S. Opperman, Kate Vandyke … Justine R. Clark … Duncan R. Hewett … Andrew C. W. Zannettino … et al.
Abstract: 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.
Keywords: Animals; Humans; Mice; Multiple Myeloma; Neoplasm Recurrence, Local; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Neoplastic Stem Cells; Stem Cell Niche; Transcriptome
Rights: © 2019 by The American Society of Hematology
RMID: 0030113790
DOI: 10.1182/blood.2018880930
Grant ID: http://purl.org/au-research/grants/nhmrc/1155678
http://purl.org/au-research/grants/nhmrc/1139237
http://purl.org/au-research/grants/nhmrc/1104031
http://purl.org/au-research/grants/nhmrc/1140996
Appears in Collections:Medicine publications

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