Tracing the origins of relapse in acute myeloid leukaemia to stem cells

Liran I. Shlush, Amanda Mitchell, Lawrence Heisler, Sagi Abelson, Stanley W.K. Ng, Aaron Trotman-Grant, Jessie J.F. Medeiros, Abilasha Rao-Bhatia, Ivana Jaciw-Zurakowsky, Rene Marke, Jessica L. McLeod, Monica Doedens, Gary Bader, Veronique Voisin, Changjiang Xu, John Douglas Mcpherson, Thomas J. Hudson, Jean C.Y. Wang, Mark D. Minden, John E. Dick

Research output: Contribution to journalArticle

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Abstract

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

Original languageEnglish (US)
Pages (from-to)104-108
Number of pages5
JournalNature
Volume547
Issue number7661
DOIs
StatePublished - Jul 6 2017
Externally publishedYes

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Acute Myeloid Leukemia
Stem Cells
Recurrence
Leukemia
Hematopoietic Stem Cells
Therapeutics
Drug Therapy
High-Throughput Nucleotide Sequencing
Investigational Therapies
Disease Management
Cell- and Tissue-Based Therapy
Transcriptome
Drug Resistance
Heterografts
Pharmaceutical Preparations
Sequence Analysis
Regeneration
Phenotype

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Shlush, L. I., Mitchell, A., Heisler, L., Abelson, S., Ng, S. W. K., Trotman-Grant, A., ... Dick, J. E. (2017). Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature, 547(7661), 104-108. https://doi.org/10.1038/nature22993

Tracing the origins of relapse in acute myeloid leukaemia to stem cells. / Shlush, Liran I.; Mitchell, Amanda; Heisler, Lawrence; Abelson, Sagi; Ng, Stanley W.K.; Trotman-Grant, Aaron; Medeiros, Jessie J.F.; Rao-Bhatia, Abilasha; Jaciw-Zurakowsky, Ivana; Marke, Rene; McLeod, Jessica L.; Doedens, Monica; Bader, Gary; Voisin, Veronique; Xu, Changjiang; Mcpherson, John Douglas; Hudson, Thomas J.; Wang, Jean C.Y.; Minden, Mark D.; Dick, John E.

In: Nature, Vol. 547, No. 7661, 06.07.2017, p. 104-108.

Research output: Contribution to journalArticle

Shlush, LI, Mitchell, A, Heisler, L, Abelson, S, Ng, SWK, Trotman-Grant, A, Medeiros, JJF, Rao-Bhatia, A, Jaciw-Zurakowsky, I, Marke, R, McLeod, JL, Doedens, M, Bader, G, Voisin, V, Xu, C, Mcpherson, JD, Hudson, TJ, Wang, JCY, Minden, MD & Dick, JE 2017, 'Tracing the origins of relapse in acute myeloid leukaemia to stem cells', Nature, vol. 547, no. 7661, pp. 104-108. https://doi.org/10.1038/nature22993
Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SWK, Trotman-Grant A et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017 Jul 6;547(7661):104-108. https://doi.org/10.1038/nature22993
Shlush, Liran I. ; Mitchell, Amanda ; Heisler, Lawrence ; Abelson, Sagi ; Ng, Stanley W.K. ; Trotman-Grant, Aaron ; Medeiros, Jessie J.F. ; Rao-Bhatia, Abilasha ; Jaciw-Zurakowsky, Ivana ; Marke, Rene ; McLeod, Jessica L. ; Doedens, Monica ; Bader, Gary ; Voisin, Veronique ; Xu, Changjiang ; Mcpherson, John Douglas ; Hudson, Thomas J. ; Wang, Jean C.Y. ; Minden, Mark D. ; Dick, John E. / Tracing the origins of relapse in acute myeloid leukaemia to stem cells. In: Nature. 2017 ; Vol. 547, No. 7661. pp. 104-108.
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AU - Trotman-Grant, Aaron

AU - Medeiros, Jessie J.F.

AU - Rao-Bhatia, Abilasha

AU - Jaciw-Zurakowsky, Ivana

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