title: Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia.
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.
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ebinger
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Erbey Ziya
authors.initials: EZ
authors.lastname: Özdemir
authors.affiliation: Anthropology and Human Genomics, Department Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, 82152 Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ziegenhain
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Tiedt
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Catarina
authors.initials: C
authors.lastname: Castro Alves
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Grunert
authors.affiliation: Children's Cancer Research Institute and St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.affiliation: Department of Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lutz
authors.affiliation: University College London Cancer Institute, London WC1E, UK.
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Turati
authors.affiliation: University College London Cancer Institute, London WC1E, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-Universität München, 80337 Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Anthropology and Human Genomics, Department Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, 82152 Martinsried, Germany.
authors.forename: Swati
authors.initials: S
authors.lastname: Parekh
authors.affiliation: 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.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: 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.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 81377 Munich, Germany.
authors.forename: Aloys
authors.initials: A
authors.lastname: Schepers
authors.affiliation: Project Group Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 93053 Regensburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Polzer
authors.affiliation: Project Group Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 93053 Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kirsch
authors.affiliation: Project Group Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 93053 Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), 85764 Neuherberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Knapp
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Hasenauer
authors.affiliation: Department of Medicine, Hematology and Oncology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Pfeifer
authors.affiliation: Children's Cancer Research Institute and St. Anna Kinderspital, Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.affiliation: Anthropology and Human Genomics, Department Biology II, Faculty of Biology, Ludwig-Maximilians-Universität München, 82152 Martinsried, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Enard
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gires
authors.affiliation: 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.
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000627:therapeutic use; D049109:Cell Proliferation; D002648:Child; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology*; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D017423:Sequence Analysis, RNA / Q000379:methods*; D059010:Single-Cell Analysis; D014407:Tumor Cells, Cultured
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc
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