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Acute Leukemias

Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56

Leukemia volume 27, pages 1637–1649 (2013)Cite this article

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Abstract

Acute myeloid leukemia with high ecotropic viral integration site-1 expression (EVI1high 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 EVI1high 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 EVI1high leukemia.

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Acknowledgements

We gratefully acknowledge Genentech for providing the Gpr56 knockout mice for the studies. This work was supported by a grant-in-aid for the third term comprehensive 10-year strategy for cancer control from the Ministry of Health and Welfare; a grant-in-aid for scientific research from The Ministry of Education, Culture, Sports, Science and Technology; a grant-in-aid for scientific research from the Japan Society for the Promotion of Science; and a Grant-in-Aid for Scientific Research on Innovative Areas.

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Authors and Affiliations

  1. Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Y Saito, K Kaneda, A Suekane, E Ichihara, S Nakahata, N Yamakawa, K Nagai & K Morishita

  2. Laboratory of Molecular Signal Transduction, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan

    N Mizuno & H Itoh

  3. Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

    K Kogawa

  4. Division of Hematology and Oncology, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki, Japan

    I Miura

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  1. Y Saito
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  2. K Kaneda
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  3. A Suekane
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Correspondence to K Morishita.

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Saito, Y., Kaneda, K., Suekane, A. et al. Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56. Leukemia 27, 1637–1649 (2013). https://doi.org/10.1038/leu.2013.75

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