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.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…These receptors may also mediate hematopoietic stem cell repopulation and retention of myeloid cells within the bone marrow niche (Saito et al, 2013). In mice, the highest expression of Adgrg3 (Gpr97) mRNA was found in the bone marrow.…”

“…Loss of ADGRG1 (GPR56) resulted in decreased granule cell adhesion to laminin and fibronectin (Koirala et al, 2009). Moreover, knockdown of ADGRG1 (GPR56) decreased cellular adhesion of acute myeloid leukemia (AML) cells to fibronectin, laminin-1, and collagen III, corresponding to a significant decrease in the number of hematopoietic stem cells (HSCs) in the bone marrow of Adgrg1 (Gpr56) knockout mice and, conversely, an increase in HSC number in spleen, liver, and peripheral blood (Saito et al, 2013). These data suggest that ADGRG1 (GPR56) plays a role in the maintenance of HSCs and/or leukemia stem cells in the bone marrow niche.…”

Dihydromunduletone Is a Small-Molecule Selective Adhesion G Protein–Coupled Receptor Antagonist

“…We conducted a chemical-screening effort to identify smallmolecule inhibitors of GPR56, an attractive therapeutic target due to its proposed roles in neurogenesis, neuromaintenance, and cancer progression (Piao et al, 2004;Shashidhar et al, 2005;Xu et al, 2006Xu et al, , 2010Yang et al, 2011;Saito et al, 2013;Hamann et al, 2015). GPR56 signals through G13 and multiple laboratories showed that GPR56 robustly activates serum response element (SRE) or serum response factor luciferase gene reporters (Iguchi et al, 2008;Kim et al, 2010;Wu et al, 2013;Stoveken et al, 2015;Kishore et al, 2016).…”

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”