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

Yoshiharu Muto, Masaaki Nishiyama (), Akihiro Nita, Toshiro Moroishi and Keiichi I. Nakayama ()
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Yoshiharu Muto: Medical Institute of Bioregulation, Kyushu University
Masaaki Nishiyama: Medical Institute of Bioregulation, Kyushu University
Akihiro Nita: Medical Institute of Bioregulation, Kyushu University
Toshiro Moroishi: Medical Institute of Bioregulation, Kyushu University
Keiichi I. Nakayama: Medical Institute of Bioregulation, Kyushu University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms16114

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