Foxm1 is essential for quiescence and maintenance of hematopoietic stem cells

Foxm1, a mammalian Forkhead Box M1 protein, is known as a typical proliferation-associated transcription factor. Here, we find that Foxm1 was essential for maintenance of hematopoietic stem cell (HSC) quiescence and self-renewal capacity in vivo in mice. Reducing expression of FOXM1 also decreased quiescence in human CD34+ HSCs and progenitor cells and its downregulation was associated with a subset of myelodysplastic syndrome (MDS). Mechanistically, Foxm1 directly bound to the promoter region of Nurr1, inducing transcription while forced expression of Nurr1 reversed the loss of quiescence observed in Foxm1-deficient cells in vivo. Thus, our studies reveal a previously unrecognized role of Foxm1 as a critical regulator of HSC quiescence and self-renewal, mediated at least in part, by control of Nurr1 expression. Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood cell lineages, and are critical for the maintenance of homeostasis of the hematopoietic system. HSCs predominantly exist in a quiescent state1, which is critical for preserving selfrenewal capacity and enabling life-long hematopoiesis2. Elucidating the molecular regulation of HSC quiescence should increase our understanding of mechanisms important Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to Z.Q. ([email protected]). University of Illinois at Chicago, 909 S. Wolcott Ave, COMRB Rm5051 M/C704, Chicago, IL 60612. Tel: 312-355-3295; Fax: 312-413-9670. Accession codes The gene expression data for the HSCs in Foxm1fl/fl and Foxm1fl/flTie2-Cre has been deposited in the Gene Expression Omnibus (GEO) under accession number: (GSE62360). AUTHOR CONTRIBUTIONS Y.H.(Yu Hou), W.L., Y.S., Z.Z., L.L and Y.H (Yong Huang). performed research; Z.Q. and Y.H.(Yu Hou) designed research and performed data analysis; W.W., J.G.Q., D.P. T.Z. and Y.Z. provided advice and new reagents/analytic tools; Z.Q., Y.H.(Yu Hou), D.P. and J.Q. wrote the paper. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. HHS Public Access Author manuscript Nat Immunol. Author manuscript; available in PMC 2016 January 31. Published in final edited form as: Nat Immunol. 2015 August ; 16(8): 810–818. doi:10.1038/ni.3204. A uhor M anscript