ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3−/− mice

Abstract

Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3 À/À HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.

Dietary low or excess levels of lipids reduced growth performance, and impaired immune function and structure of head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella) under the infection of Aeromonas hydrophila

“…In rat, a high-fat diet increased reactive oxygen species (ROS) production in the liver [20]. It was reported that ROS upregulates TOR mRNA expression in mouse monocytes [21]. According to these studies, it follows that lipids may affect the production of humoral compounds, cytokines, IkBa/NF-kB and TOR/ S6K1 signalling molecules in fish immune organs, and the possibility is worthy of investigation.…”

FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

“…Here, we show that FOXO3, which is essential for the regulation of oxidative stress in HSC (12,13,21,35), is a key factor in the primitive hematopoietic cell DNA damage response, specifically in base excision repair, and it protects HSPC from oxidative DNA damage under homeostasis. These findings raise the possibility that DNA damage accrual as a result of loss of FOXO3 function, as may occur with age, promotes HSC aging (32)(33)(34), predisposes HSPCs to premature aging, and/or contributes to hematopoietic stem cell malignant transformation (18,23,29,30).…”

“…Loss of FOXO3 results in oxidative stress-mediated myeloproliferation that does not progress, at least not rapidly enough to have been detected, toward leukemia (12,13,21). FOXO3 is intimately involved in hematopoietic malignancies, as FOXO3 is found in chromosomal translocations of human acute myeloid leukemia (22) and is inhibited in malignant hematopoietic cells (18,(23)(24)(25)(26)(27)(28).…”

Mitophagy in hematopoietic stem cells

“…These defects can be reversed by antioxidant treatment, implicating excessive ROS production as a detrimental signal for HSCs' function and survival. [43][44][45] MTOR is a nutrient sensor that balances cell growth with nutrient availability by regulating cellular functions, including nutrient uptake, protein synthesis, and autophagy. 46 The MTOR pathway also regulates energy metabolism via transcriptional control of mitochondrial oxidative function through the YY1-PPARGC1A transcriptional complex.…”