MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cell (MSC) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes in MSC epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1.1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU-Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation, and cell metabolism networks in MDS-MSCs.

[Alcohol and health: attitudes, habits and knowledge of a group of young physicians]. / Alcool e salute: atteggiamento, abitudini e conoscenze di un gruppo di giovani medici.

By means of a set of questions the Authors analyze the habits, the attitudes and the knowledge of a group of young medical doctors, concerning the problem of alcohol and health. People interviewed are 873 Medical Reserve Officer Cadets who attended the propedeutic course at the Military Medical School of Florence from September 1987 to May 1988. These people formed a considerable part of the young male medical doctors who had graduated in Italy the previous year. This set of questions is based on the multiple choice system, with 37 questions divided in 4 sections: 1. access to the set of questions with personal information and previous studies; 2. habits and attitudes of the person concerning the consumption of alcoholic drinks; 3. general knowledge of some legal and epidemiological aspects; 4. specific knowledge of the alcohol as a risk factor and of the diagnosis and the prevention of the alcohol related pathologies. The central role of the university in acquiring the knowledge of people interviewed, clearly results from the analysis of the answers. Only few young people assert they got their knowledge from scientific publications. The belief that drinking alcohol with the meals is healthy, is more evident in the South than in the North of Italy; at the same time the prevalence of alcohol related diseases seems to increase moving from Southern to Northern Italy. The more moderate attitude of parents in Northern Italy, seems to be somehow affected by the prevalence of alcohol related diseases in this area. Most young doctors do not drink either light alcoholic drinks or spirits to excess, however 9 people claim to drink wine both with the meals and between, and some 20 claim to drink spirits once a day or even more. A remarkable part of people interviewed seems not to have a full understanding of self-definitions as "abstemious", "moderate drinker", "normal drinker", "heavy drinker". These definitions often do not fit with the quantities declared. The knowledge about metabolism and immediate effects of alcohol is not always proper: it is particularly surprising that more than a third of doctors think that alcohol warms the body and helps to bear low temperature. The poor knowledge of the epidemiological aspects of alcohol consumption is not acceptable, testifying the remarkable difficulty in having a global vision and a right dimension of the problem. In particular an inadequate evaluation of the seriousness of the alcohol related pathologies, considered insufficiently represented among the death causes by one fifth, emerges from the answers.(ABSTRACT TRUNCATED AT 400 WORDS)