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Nature. 2017 Jul 6;547(7661):104-108. doi: 10.1038/nature22993. Epub 2017 Jun 28.

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

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Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Division of Hematology Rambam Healthcare Campus, Haifa 31096, Israel.
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario M5G 2M9, Canada.


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.

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