title: Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56.
abstract: Acute myeloid leukemia with high ecotropic viral integration site-1 expression (EVI1(high) AML) is classified as a refractory type of leukemia with a poor prognosis. To provide new insights into the prevention and treatment of this disease, we identified the high expression of EVI1-regulated G protein-coupled receptor 56 (GPR56), and the association of high cell adhesion and antiapoptotic activities in EVI1(high) AML cells. Knockdown of GPR56 expression decreased the cellular adhesion ability through inactivation of RhoA signaling, resulting in a reduction of cellular growth rates and enhanced apoptosis. Moreover, in Gpr56(-/-) mice, the number of hematopoietic stem cells (HSCs) was significantly decreased in the bone marrow (BM) and, conversely, was increased in the spleen, liver and peripheral blood. The number of Gpr56(-/-) HSC progenitors in the G0/G1-phase was significantly reduced and was associated with impaired cellular adhesion. Finally, the loss of GPR56 function resulted in a reduction of the in vivo repopulating ability of the HSCs. In conclusion, GPR56 may represent an important GPCR for the maintenance of HSCs by acting as a co-ordinator of interactions with the BM osteosteal niche; furthermore, this receptor has the potential to become a novel molecular target in EVI1(high) leukemia.
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Kaneda
authors.forename: A
authors.initials: A
authors.lastname: Suekane
authors.forename: E
authors.initials: E
authors.lastname: Ichihara
authors.forename: S
authors.initials: S
authors.lastname: Nakahata
authors.forename: N
authors.initials: N
authors.lastname: Yamakawa
authors.forename: K
authors.initials: K
authors.lastname: Nagai
authors.forename: N
authors.initials: N
authors.lastname: Mizuno
authors.forename: K
authors.initials: K
authors.lastname: Kogawa
authors.forename: I
authors.initials: I
authors.lastname: Miura
authors.forename: H
authors.initials: H
authors.lastname: Itoh
authors.forename: K
authors.initials: K
authors.lastname: Morishita
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D001853:Bone Marrow / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011519:Proto-Oncogenes; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C524781:Adgrg1 protein, mouse; C499305:Mecom protein, mouse