title: A 17-gene stemness score for rapid determination of risk in acute leukaemia.
abstract: Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC+and 89 LSC-cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Stanley W K
authors.initials: SW
authors.lastname: Ng
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Kennedy
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Weihsu C
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: McLeod
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Narmin
authors.initials: N
authors.lastname: Ibrahimova
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arruda
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Andreea
authors.initials: A
authors.lastname: Popescu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Andre C
authors.initials: AC
authors.lastname: Schuh
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Yee
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University of Munich, 81377 Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Görlich
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Münster, 48149 Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Department of Internal Medicine III, University of Munich, 81377 Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Münster, 48149 Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, 10117 Berlin, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wörmann
authors.affiliation: Jean-Pierre AUBERT Research Center UMR-S 1172, Institute for Cancer Research Lille, 59045 Lille, France.
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.affiliation: University Hospital of Lille, Center of Pathology, Laboratory of Hematology, 59037 Lille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Saint-Louis Hospital, Department of Hematology, University of Paris Diderot, 75010 Paris, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Department of Internal Medicine III, University of Munich, 81377 Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Metzeler
authors.affiliation: Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
authors.affiliation: Department of Hematology, Erasmus University Medical Centre, 3015 CE Rotterdam, the Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Department of Hematology, Erasmus University Medical Centre, 3015 CE Rotterdam, the Netherlands.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
mesh_terms: D000465:Algorithms; D000818:Animals; D015331:Cohort Studies; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D018570:Risk Assessment; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D059467:Transcriptome; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays