title: GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo.
abstract: Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy, which is initiated and driven by a rare fraction of leukemia stem cells (LSCs). Despite the difficulties of identifying a common LSC phenotype, there is increasing evidence that high expression of stem cell gene signatures is associated with poor clinical outcome. Identification of functionally distinct subpopulations in this disease is therefore crucial to dissecting the molecular machinery underlying LSC self-renewal. Here, we combined next-generation sequencing technology with in vivo assessment of LSC frequencies and identified the adhesion G protein-coupled receptor 56 (GPR56) as a novel and stable marker for human LSCs for the majority of AML samples. High GPR56 expression was significantly associated with high-risk genetic subgroups and poor outcome. Analysis of GPR56 in combination with CD34 expression revealed engraftment potential of GPR56(+)cells in both the CD34(-)and CD34(+)fractions, thus defining a novel LSC compartment independent of the CD34(+)CD38(-)LSC phenotype.
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada; Department of Internal Medicine IV, Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany;
authors.forename: Caroline
authors.identifier: http://orcid.org/0000-0001-9716-5909
authors.initials: C
authors.lastname: Pabst
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Centre de Recherche en Infectiologie du Centre Hospitalier de l'Université de Laval, Quebec City, QC, Canada;
authors.forename: Anne
authors.initials: A
authors.lastname: Bergeron
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada; Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada;
authors.forename: Vincent-Philippe
authors.initials: VP
authors.lastname: Lavallée
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yeh
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Patrick
authors.initials: P
authors.lastname: Gendron
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Gudmundur L
authors.initials: GL
authors.lastname: Norddahl
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Jana
authors.identifier: http://orcid.org/0000-0002-9839-265X
authors.initials: J
authors.lastname: Krosl
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Isabel
authors.identifier: http://orcid.org/0000-0002-1216-3240
authors.initials: I
authors.lastname: Boivin
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Eric
authors.identifier: http://orcid.org/0000-0002-6875-0380
authors.initials: E
authors.lastname: Deneault
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Centre de Recherche en Infectiologie du Centre Hospitalier de l'Université de Laval, Quebec City, QC, Canada;
authors.forename: Jessica
authors.identifier: http://orcid.org/0000-0002-6297-3874
authors.initials: J
authors.lastname: Simard
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Suzan
authors.identifier: http://orcid.org/0000-0002-2682-4732
authors.initials: S
authors.lastname: Imren
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada;
authors.forename: Geneviève
authors.initials: G
authors.lastname: Boucher
authors.affiliation: Department of Pediatrics, Research Institute of the McGill University Health Centre, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Kolja
authors.identifier: http://orcid.org/0000-0001-9061-8856
authors.initials: K
authors.lastname: Eppert
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand;
authors.forename: Stefan K
authors.identifier: http://orcid.org/0000-0002-2202-9088
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Keith
authors.identifier: http://orcid.org/0000-0003-0540-7005
authors.initials: K
authors.lastname: Humphries
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada; Department of Computer Science and Operations Research, University of Montreal, Montreal, QC, Canada;
authors.forename: Sébastien
authors.identifier: http://orcid.org/0000-0001-5477-1386
authors.initials: S
authors.lastname: Lemieux
authors.affiliation: Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Department of Medicine, University of Montreal, Montreal, QC, Canada;
authors.forename: Josée
authors.initials: J
authors.lastname: Hébert
authors.affiliation: Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada; Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Department of Medicine, University of Montreal, Montreal, QC, Canada;
authors.forename: Guy
authors.initials: G
authors.lastname: Sauvageau
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Centre de Recherche en Infectiologie du Centre Hospitalier de l'Université de Laval, Quebec City, QC, Canada; CHU de Québec Hôpital Enfant-Jésus, Quebec City, QC, Canada; and Department of Medicine, University Laval, Quebec City, QC, Canada.
authors.forename: Frédéric
authors.identifier: http://orcid.org/0000-0003-0024-3611
authors.initials: F
authors.lastname: Barabé
mesh_terms: D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism* / Q000502:physiology; D016019:Survival Analysis
chemical_list: C118925:ADGRG1 protein, human; D014408:Biomarkers, Tumor; D043562:Receptors, G-Protein-Coupled