title: Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress.
abstract: The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steady-state hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reactive oxygen species scavenging by N-acetyl cysteine or stabilization of hypoxia signaling by knockdown of the von-Hippel-Lindau (VHL) protein led to reversal of the effects of Meis1 deletion. The results of the present study demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45236, USA.
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Unnisa
authors.forename: Jason P
authors.initials: JP
authors.lastname: Clark
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Roychoudhury
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thomas
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
mesh_terms: D000818:Animals; D002453:Cell Cycle; D015687:Cell Hypoxia; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D017382:Reactive Oxygen Species; D014157:Transcription Factors