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AML1/Runx1 Negatively Regulates Quiescent Hematopoietic Stem Cells in Adult Hematopoiesis¹

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Transcription factor AML1/Runx1, initially isolated from the t(8;21) chromosomal translocation in human leukemia, is essential for the development of multilineage hematopoiesis in mouse embryos. AML1 negatively regulates the number of immature hematopoietic cells in adult hematopoiesis, whereas it is required for megakaryocytic maturation and lymphocytic development. However, it remains yet to be determined how AML1 contributes to homeostasis of hematopoietic stem cells (HSCs). To address this issue, we analyzed in detail HSC function in the absence of AML1. Notably, cells in the Hoechst 33342 side population fraction are increased in number in AML1-deficient bone marrow, which suggests enrichment of quiescent HSCs. We also found an increase in HSC number within the AML1-deficient bone marrow using limiting dilution bone marrow transplantation assays. These results indicate that the number of quiescent HSCs is negatively regulated by AML1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology (KAKENHI 18013014 to M.K.), Japan Society for the Promotion of Science (Grant-in-Aid for Fellows 17-10666 to M.I.), and the Ministry of Health, Labour and Welfare (Health and Labour Sciences Research Grants to M.K.).

² Address correspondence and reprint requests to Dr. Mineo Kurokawa, Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan. E-mail address: kurokawa-tky{at}umin.ac.jp

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; 7-AAD, 7-aminoactinomycin D; SP, side population; KSL, lineage-negative, c-Kit-positive, and Sca-1-positive; cKO, conditional knockout; CRU, competitive repopulating unit; Ct, cycle threshold; GMP, granulocyte-macrophage progenitor; CMP, common myeloid progenitor.