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Cancer Cell. 2016 Dec 12;30(6):849-862. doi: 10.1016/j.ccell.2016.11.002. Epub 2016 Dec 1.

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia.

Author information

1
Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
2
Anthropology and Human Genomics, Department Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, 82152 Martinsried, Germany.
3
Children's Cancer Research Institute and St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
4
Department of Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
5
University College London Cancer Institute, London WC1E, UK.
6
Institute of Pathology, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
7
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; German Consortium for Translational Cancer Research (DKTK), Partnering Site, Munich, 81377 Munich, Germany.
8
Project Group Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 93053 Regensburg, Germany.
9
Institute of Computational Biology, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 85764 Neuherberg, Germany.
10
Institute of Computational Biology, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 85764 Neuherberg, Germany; Department of Mathematics, Technische Universität München (TUM), 85748 Munich, Germany.
11
Department of Medicine, Hematology and Oncology, Goethe University, 60590 Frankfurt, Germany.
12
Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
13
Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany; German Consortium for Translational Cancer Research (DKTK), Partnering Site, Munich, 81377 Munich, Germany; Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University München, 80337 Munich, Germany. Electronic address: irmela.jeremias@helmholtz-muenchen.de.

Abstract

Tumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression profiling revealed their similarity to primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD). Therapeutically adverse characteristics were reversible, as resistant, dormant cells became sensitive to treatment and started proliferating when dissociated from the in vivo environment. Our data suggest that ALL patients might profit from therapeutic strategies that release MRD cells from the niche.

KEYWORDS:

Cancer stem cells; RNA single-cell sequencing; acute lymphoblastic leukemia; dormant tumor cells; minimal residual disease (MRD); patient-derived xenograft (PDX) cells; primary patients' ALL MRD cells; treatment resistance

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PMID:
27916615
PMCID:
PMC5156313
DOI:
10.1016/j.ccell.2016.11.002
[Indexed for MEDLINE]
Free PMC Article

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