Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells

Nat Commun. 2017 Jul 17;8:16114. doi: 10.1038/ncomms16114.

Abstract

Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Case-Control Studies
  • Cell Self Renewal / genetics*
  • Down-Regulation
  • F-Box Proteins / genetics*
  • F-Box Proteins / metabolism
  • Gene Knockout Techniques
  • Hematopoietic Stem Cells / metabolism*
  • Homeostasis / genetics*
  • Humans
  • Iron / metabolism*
  • Iron Regulatory Protein 2 / genetics
  • Mice
  • Mice, Knockout
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism
  • Oxidative Stress / genetics*
  • Ubiquitin-Protein Ligase Complexes / genetics*
  • Ubiquitin-Protein Ligase Complexes / metabolism

Substances

  • F-Box Proteins
  • FBXL5 protein, human
  • FBXL5 protein, mouse
  • Iron
  • Ubiquitin-Protein Ligase Complexes
  • Iron Regulatory Protein 2