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 Seeliger & 14 others Mark Novotny, Roger S. Lasken, Tuan V. Nguyen, Babatunde O. Oyajobi, Dana Aftab, Alexander Swarbrick, Belinda Parker, Duncan Hewett, Dirk Hose, Karin Vanderkerken, Andrew Zannettino, Ido Amit, Tri Giang Phan, Peter I. Croucher

Research output: Contribution to journalArticle

5 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 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.

LanguageEnglish
Pages30-43
Number of pages14
JournalBlood
Volume134
Issue number1
DOIs
Publication statusPublished - 4 Jul 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Khoo, W. H., Ledergor, G., Weiner, A., Roden, D. L., Terry, R. L., McDonald, M. M., ... Croucher, P. I. (2019). A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. Blood, 134(1), 30-43. https://doi.org/10.1182/blood.2018880930
Khoo, Weng Hua ; Ledergor, Guy ; Weiner, Assaf ; Roden, Daniel L. ; Terry, Rachael L. ; McDonald, Michelle M. ; Chai, Ryan C. ; De Veirman, Kim ; Owen, Katie L. ; Opperman, Khatora S. ; Vandyke, Kate ; Clark, Justine R. ; Seckinger, Anja ; Kovacic, Natasa ; Nguyen, Akira ; Mohanty, Sindhu T. ; Pettitt, Jessica A. ; Xiao, Ya ; Corr, Alexander P. ; Seeliger, Christine ; Novotny, Mark ; Lasken, Roger S. ; Nguyen, Tuan V. ; Oyajobi, Babatunde O. ; Aftab, Dana ; Swarbrick, Alexander ; Parker, Belinda ; Hewett, Duncan ; Hose, Dirk ; Vanderkerken, Karin ; Zannettino, Andrew ; Amit, Ido ; Phan, Tri Giang ; Croucher, Peter I. / A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. In: Blood. 2019 ; Vol. 134, No. 1. pp. 30-43.
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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.",
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Khoo, WH, Ledergor, G, Weiner, A, Roden, DL, Terry, RL, McDonald, MM, Chai, RC, De Veirman, K, Owen, KL, Opperman, KS, Vandyke, K, Clark, JR, Seckinger, A, Kovacic, N, Nguyen, A, Mohanty, ST, Pettitt, JA, Xiao, Y, Corr, AP, Seeliger, C, Novotny, M, Lasken, RS, Nguyen, TV, Oyajobi, BO, Aftab, D, Swarbrick, A, Parker, B, Hewett, D, Hose, D, Vanderkerken, K, Zannettino, A, Amit, I, Phan, TG & Croucher, PI 2019, 'A niche-dependent myeloid transcriptome signature defines dormant myeloma cells', Blood, vol. 134, no. 1, pp. 30-43. https://doi.org/10.1182/blood.2018880930

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

In: Blood, Vol. 134, No. 1, 04.07.2019, p. 30-43.

Research output: Contribution to journalArticle

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T1 - A niche-dependent myeloid transcriptome signature defines dormant myeloma cells

AU - Khoo, Weng Hua

AU - Ledergor, Guy

AU - Weiner, Assaf

AU - Roden, Daniel L.

AU - Terry, Rachael L.

AU - McDonald, Michelle M.

AU - Chai, Ryan C.

AU - De Veirman, Kim

AU - Owen, Katie L.

AU - Opperman, Khatora S.

AU - Vandyke, Kate

AU - Clark, Justine R.

AU - Seckinger, Anja

AU - Kovacic, Natasa

AU - Nguyen, Akira

AU - Mohanty, Sindhu T.

AU - Pettitt, Jessica A.

AU - Xiao, Ya

AU - Corr, Alexander P.

AU - Seeliger, Christine

AU - Novotny, Mark

AU - Lasken, Roger S.

AU - Nguyen, Tuan V.

AU - Oyajobi, Babatunde O.

AU - Aftab, Dana

AU - Swarbrick, Alexander

AU - Parker, Belinda

AU - Hewett, Duncan

AU - Hose, Dirk

AU - Vanderkerken, Karin

AU - Zannettino, Andrew

AU - Amit, Ido

AU - Phan, Tri Giang

AU - Croucher, Peter I.

PY - 2019/7/4

Y1 - 2019/7/4

N2 - 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.

AB - 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.

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Khoo WH, Ledergor G, Weiner A, Roden DL, Terry RL, McDonald MM et al. A niche-dependent myeloid transcriptome signature defines dormant myeloma cells. Blood. 2019 Jul 4;134(1):30-43. https://doi.org/10.1182/blood.2018880930