Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1–/– phenotype. Here we demonstrate that cells derived from Bmi1–/– mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1–/– mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization. PTC596 induced apoptosis in a p53-independent manner. PTC596 induced apoptosis along with the reduction of MCL-1 and phosphorylated AKT in patient-derived CD34+CD38low/− stem/progenitor cells. Mouse xenograft models demonstrated in vivo anti-leukemia activity of PTC596, which inhibited leukemia cell growth in vivo while sparing normal hematopoietic cells. Our results indicate that PTC596 deserves further evaluation in clinical trials for refractory or relapsed AML patients, especially for those with unfavorable complex karyotype or therapy-related AML that are frequently associated with p53 mutations.
Taihu Lake is the third largest freshwater lake in China and serves as a drinking water source for~30 million residents. Tiaoxi River is one of the main rivers connected to this lake and contributes >60% of the source water. Taihu Lake has been facing various environmental issues; therefore, it is important to study the water quality of its inflow rivers. This study aimed to evaluate the physico-chemical and microbiological characteristics of Tiaoxi River and to determine the spatial and seasonal variations in the water quality. Water samples were collected from 25 locations across the Tiaoxi River in three seasons in 2014-2015. Fourteen water quality parameters including multiple nutrients and indicator bacteria were assessed, and the data analyzed by multivariate statistical analyses. The physico-chemical analysis showed high levels (>1 mg/L) of total nitrogen (TN) in all locations for all seasons. Total phosphorus (TP), nitrite-N (NO 2 -N), and ammonium-N (NH 4 -N) exceeded the acceptable limits in some locations and fecal coliform counts were high (>250 CFU/100 mL) in 15 locations. Hierarchical cluster analysis showed that the sampling sites could be grouped into three clusters based on water quality, which were categorized as low, moderate, and high pollution areas. Principal component analysis (PCA) applied to the entire dataset identified four principal components which explained 83% of the variation; pH, conductivity, TP, and NO 3 -N were found to be the key parameters responsible for variations in water quality. The overall results indicated that some of the sampling locations in the Tiaoxi River are heavily contaminated with pollutants from various sources which can be correlated with land use patterns and anthropogenic activities.
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