Quantitative analysis of redox proteome reveals oxidation-sensitive protein thiols acting in fundamental processes of developmental hematopoiesis.

Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behavior in normal and malignant hematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4,438 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenic changes to oxidation state of thiols in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified oxidation changes to thiols acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signaling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukemia.

New insights into the cytoplasmic function of PML.

PML is a tumour suppressor inactivated in Acute Promyelocytic Leukaemia (APL). PML is the essential component of a subnuclear structure called the PML nuclear body (PML-NB), which is disrupted in APL. By targeting different cellular proteins to this structure, PML can either hamper or potentiate their functions. The PML transcript undergoes alternative splicing to generate both nuclear and cytoplasmic isoforms. Most of the research in this field has focused its attention on studying nuclear PML. Nevertheless, new exciting studies show that cytoplasmic PML may control essential cellular functions, thus opening new avenues for investigation.

Non-HDL cholesterol predicts coronary heart disease in primary prevention: findings from an Italian 40-69 year-old cohort in general practice.

OBJECTS: Non-HDL cholesterol is now recommended as an index of risk associated with combined dyslipidemia, and it has also been found useful in predicting coronary heart disease (CHD) risk in patients with diabetes. We studied the association between known CHD risk factors, enclosed non-HDL cholesterol, and a "high CHD risk condition", i.e. a "5-years CHD risk >15%" in general practice. METHODS: We studied 4,085 40-69 year-old diabetic (no. 489) and non-diabetic (no. 3,596) individuals from an opportunistic cohort. Cross-sectional descriptive statistics, and age- and gender-adjusted multiple logistic exponential betas have been calculated. RESULTS: About 12% of the participants had diabetes. Age- and gender-adjusted comparison showed that all the study variables were significantly worse in diabetic vs. non-diabetic individuals (except cigarette smoking, total blood cholesterol and the ratio of total to HDL cholesterol). They had a mean "5-year CHD-risk" significantly higher than non-diabetic individuals (18.8+/-11.9% vs 7.5+/-6.9%, P<0.01), and a four-fold prevalence of "5-years CHD risk >15%" (55.4% vs 11.1%, P<0.01). As to diabetic individuals, the study variables associated to a "high CHD risk condition" were cigarette smoking, systolic blood pressure, and non-HDL blood cholesterol levels. As to non-diabetic individuals cigarette smoking, systolic blood pressure, and HDL (inversely) and non-HDL blood cholesterol levels were associated to a "high CHD risk condition". CONCLUSIONS: Non-HDL cholesterol--and cigarette smoking and systolic blood pressure--strongly predicted a "high CHD risk condition" both in diabetic and non-diabetic individuals.