Highlights d HSCs permanently remodel the mitochondrial network after replicative stress d HSCs keep dysfunctional mitochondria because of Drp1 loss, causing functional decline d HSCs accumulate dysfunctional mitochondria through asymmetric division d HSC attrition is due to asynchrony in cell cycle and biosynthetic gene expression

Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.

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Bone marrow failure syndromes (BMF) are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells (HSC). BMFs can be acquired during bone marrow stress or innate are associated with driver genetic mutations. BMFs are at higher risks of developing secondary neoplasms, including myelodysplastic syndromes and leukemia. Despite the identification of genetic driver mutations, the hematopoietic presentation of the disease is quite heterogeneous raising the possibility that non-genetic factors contribute to the pathogenesis of the disease. The role of inflammation has emerged as an important contributing factors, but remain to be understood in detail. In this study, we examined the effect of increased TGFβ signaling in combination or not with an acute innate immune challenge using polyinosinc:polycytidilic acid (pIC) on the hematopoietic system without genetic mutations. We show that acute rounds of pIC alone drive a benign age-related myeloid cell expansion, increased TGFβ signaling alone causes a modest anemia on old mice. In sharp contrast, increased TGFβ signaling plus acute pIC challenge result in chronic pancytopenia, expanded hematopoietic stem and progenitor pools, and increased bone marrow dysplasia 3-4 months after stress, phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with increased mitochondrial content, increased reactive oxygen species and enhanced caspase-1 activity. Our results suggest that chronic increased TGFβ signaling modifies the memory of an acute immune response to drive bone marrow failure without the need for pre-existing genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.

High concentrations of fluoride in the body may cause toxic effects. Here, we investigated the effects of fluoride on the structure, function, and proteome of a cortical collecting duct epithelium in vitro. Kidney tubule cells (M-1) were chosen because the concentration of fluoride in the kidney is 4-5-fold higher than that in plasma. Mouse M-1 cell monolayers were incubated in fluoride-containing media, and the amiloride-sensitive short-circuit current and transepithelial resistance were measured. The Young's modulus of the epithelium was determined using atomic force microscopy, and the effect of fluoride on epithelial structure was assessed using scanning and transmission electron microscopy, and immunofluorescence. Differences in the expression of membrane proteins were evaluated using proteomics and bioinformatics. Fluoride exposure reduced both transepithelial Na transport and resistance. The IC for fluoride was ∼300 µM for both effects, and the half-times for the decays of ion transport and resistance were 8.4 h and 3.6 days, respectively. Fluoride treatment did not affect the sensitivity of Na transport to amiloride. The Young's modulus of the epithelium was also unaffected by fluoride; however, the functional effects of fluoride were accompanied by marked structural effects. Proteomic analysis revealed changes in expression of a number of proteins, and particularly mitochondrial proteins. Treatment with fluoride had profound effects on the structure, function and proteome of a model cortical collecting duct epithelium. Significantly, however, these effects were produced only at concentrations considerably higher than those likely to be encountered in vivo. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1455-1467, 2017.

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