A Niche-Dependent Myeloid Transcriptome Signature Defines Dormant Myeloma Cells

Weng Hua Khoo, Guy Ledergor, Assaf Weiner, Daniel L Roden, Rachael L Terry, Michelle M McDonald, Ryan C Chai, Kim De Veirman, Katie L Owen, Khatora S Opperman, Kate Vandyke, Justine R Clark, Anja Seckinger, Natasa Kovacic, Akira Nguyen, Sindhu T Mohanty, Jessica A Pettitt, Ya Xiao, Alexander P Corr, Christine SeeligerMark Novotny, Roger S Lasken, Tuan V Nguyen, Babatunde O Oyajobi, Dana Aftab, Alexander Swarbrick, Belinda Parker, Duncan R Hewett, Dirk Hose, Karin Vanderkerken, Andrew C W Zannettino, Ido Amit, Tri Giang Phan, Peter I Croucher

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)30-43
Number of pages14
JournalBlood
Volume134
Issue number1
Early online date25 Apr 2019
DOIs
Publication statusPublished - 4 Jul 2019

Bibliographical note

© 2019 by The American Society of Hematology.

Keywords

  • Myeloma Cells
  • survival
  • multiple myeloma

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