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

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.

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

“…Previous studies have indicated that iron homeostasis is crucial for various kinds of stem cell. For example, iron overload can impact the self‐renewal and function of hematopoietic stem cells and progenitor cells [23,24], whereas iron deficiency impairs the pluripotency of hESCs/hiPSCs [15]. Besides, it has been reported that iron deficiency inhibited the expression of stemness markers and spherogenesis in cancer stem cells [25].…”

Iron Homeostasis Determines Fate of Human Pluripotent Stem Cells Via Glycerophospholipids-Epigenetic Circuit

“…Growing evidence has shown that iron homeostasis is critical for stem cells. For example, iron overload can affect the self‐renewal, frequency, and functioning of hematopoietic stem and progenitor cells . Thus far, little is known regarding the role of iron homeostasis in maintaining the biological property of PSCs.…”

Repurposing Antibacterial AM404 As a Potential Anticancer Drug for Targeting Colorectal Cancer Stem-Like Cells

“…Several pathways including Wnt-β catenin, PIK3CA/AKT/PTEN, and NF-κB, have been postulated as targets for NSAIDs [54]. FBXL5 has previously been interpreted as oncogene whilst its association in iron regulation is required for HSC self-renewal [52]. In CRC progression, FBXL5 has shown to induce cell proliferation, growth, tumorigenesis and inhibit cell apoptosis by modulating PTEN/PI3K/AKT signalling and its overexpression resulted in high tumour formation ability [24,27].…”

“…When used in FBXL5-KO-cells, AM404 showed sensitivity and further additive effect in preventing cells invasion suggesting AM404 as a new compound to target FBXL5 in blocking CRC cell migration. We currently do not have an in vivo intestinal/colon model that implicit FBXL5 as a potential therapeutic target for cancer stem cells, although an essential role of FBXL5-mediated cellular iron homeostasis in the maintenance of hematopoietic stem cells has already been reported [52].…”

“…FBXL5 (F-box and leucine-rich repeat protein 5), also known as FBL4 and FBL5, is a member of the F-box protein family, characterized by an F-box motif consisting of 40 amino acids [24,26,51]. It is predominantly an iron and oxygen-regulated SCF-type E3 ubiquitin ligase containing an N-terminal hemerythrin-like domain, α-helix-rich structure [51,52]. Therefore, we initially sought to examine whether the expression of FBXL5 was altered in patients' colorectal cancers.…”