title: GPR56 contributes to the development of acute myeloid leukemia in mice.
abstract: The G protein-coupled receptor 56 (GPR56) was identified as part of the molecular signature of functionally validated leukemic stem cells isolated from patients with acute myeloid leukemia (AML). This report now demonstrates particularly high expression of GPR56 in patients with mutant NPM1 and FLT3-length mutation and association of high GPR56 expression with inferior prognosis in a large patient cohort treated in two independent multicenter phase III trials. Functional relevance of GPR56 expression was validated in mice, in which co-expression of Gpr56 significantly accelerated HOXA9-induced leukemogenesis and vice versa knockdown of Gpr56 delayed onset of HOXA9/MEIS1-induced AML. Overexpression of Gpr56 grossly changed the molecular phenotype of Hoxa9-transduced cells affecting pathways involved in G protein-coupled receptors (GPRCs) and associated intracellular signaling. Blockage of surface GPR56 by an anti-GPR56 antibody successfully impaired engraftment of primary human AML cells. In summary, these data demonstrate that high expression of GPR56 is able to contribute to AML development and characterize the GPR56 as a potential novel target for antibody-mediated antileukemic strategies.
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Daria
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Kirsten
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Muranyi
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mulaw
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ihme
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kechter
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hollnagel
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Feuring-Buske
authors.affiliation: Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Buske
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D005260:Female; D064593:Heterografts; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D008297:Male; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D000090243:Nucleophosmin; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000090243:Nucleophosmin; D043562:Receptors, G-Protein-Coupled; C118925:ADGRG1 protein, human; C524781:Adgrg1 protein, mouse; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C097899:homeobox protein HOXA9