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Blood. 2019 Apr 25. pii: blood.2018880930. doi: 10.1182/blood.2018880930. [Epub ahead of print]

A Niche-Dependent Myeloid Transcriptome Signature Defines Dormant Myeloma Cells.

Author information

1
Bone Biology, Garvan Institute of Medical Research, Australia.
2
Immunology, Weizmann Institute of Science, United States.
3
Weizmann Institute of Science.
4
Garvan Institute of Medical Research.
5
Personalised Medicine, The Children's Cancer Institute, Australia.
6
Bone, Garvan Institute, Australia.
7
Garvan Institute of Medical Research, Australia.
8
Vrije Universiteit Brussel (VUB), Belgium.
9
La Trobe University.
10
South Australian Health and Medical Research Institute, Australia.
11
Adelaide Medical School, University of Adelaide, Australia.
12
Faculty of Health and Medical Sciences, University of Adelaide, Australia.
13
Medizinische Klinik V, Universitätsklinikum Heidelberg, Germany.
14
Department of Anatomy, University of Zagreb School of Medicine, Croatia, Republic of.
15
Bone Division, Garvan Institute of Medical Research, Australia.
16
J. Craig Venter Institute, United States.
17
J. Craig Venter Institute.
18
Bone Biology Division, Garvan Institute of Medical Research, Australia.
19
Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, United States.
20
Exelixis, Inc., United States.
21
La Trobe Institute for Molecular Science, Australia.
22
University of Adelaide, Australia.
23
Vrije Universiteit Brussel (VUB).
24
Adelaide Medical School, The University of Adelaide, Australia.
25
Weizmann Institute of Science, Israel.
26
Immunology, Garvan Institute of Medical Research, Australia.
27
Bone Biology, Garvan Institute of Medical Research, Australia p.croucher@garvan.org.au.

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 co-culture 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 co-regulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance (MGUS) 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 to a two-fold 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 are potential drug targets to eradicate dormant myeloma cells.

PMID:
31023703
DOI:
10.1182/blood.2018880930

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