Search

DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases. Consequently, the aim of our study was to analyze the modifications of DNA methylation profiles of MSCs induced by MDS or AML. MSCs from MDS/AML patients were characterized via 5-methylcytosine quantification, gene expression profiles of key regulators of DNA methylation, identification of differentially methylated regions (DMRs) by methylome array, and quantification of DMR-coupled genes expression. MDS and AML-MSCs displayed global hypomethylation and under-expression of DNMT1 and UHRF1. Methylome analysis revealed aberrant methylation profiles in all MDS and in a subgroup of AML-MSCs. This aberrant methylation was preferentially found in the sequence of homeobox genes, especially from the HOX family (HOXA1, HOXA4, HOXA5, HOXA9, HOXA10, HOXA11, HOXB5, HOXC4, and HOXC6), and impacted on their expression. These results highlight modifications of DNA methylation in MDS/AML-MSCs, both at global and focal levels dysregulating the expression of HOX genes well known for their involvement in leukemogenesis. Such DNA methylation in MSCs could be the consequence of the malignant disease or could participate in its development through defective functionality or exosomal transfer of HOX transcription factors from MSCs to hematopoietic cells., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Simple Summary: Pesticide exposure is a public health concern. Two recent studies reported that exposure of normal primary bone marrow mesenchymal stem/stromal cells (BM-MSCs) to low-dose pesticide mixture induces deleterious consequences, such as oxidative stress, senescence, accelerated aging and increased sensitivity to oncogenic hits. Here, we show that exposure to this mixture decreases aldehyde dehydrogenase-2 (ALDH2) activity, with a concomitant increase in acetaldehyde level and DNA damage and alters the MSC capacity to support primitive hematopoiesis. Similar abnormalities were observed in bone marrow-MSCs from patients suffering from myelodysplastic syndrome (MDS), suggesting a role of pesticide-induced ALDH2 inhibition in the pathophysiology of this pre-leukemic disease. (1) Background: The impact of occupational exposure to high doses of pesticides on hematologic disorders is widely studied. Yet, lifelong exposure to low doses of pesticides, and more particularly their cocktail effect, although poorly known, could also participate to the development of such hematological diseases as myelodysplastic syndrome (MDS) in elderly patients. (2) Methods: In this study, a cocktail of seven pesticides frequently present in water and food (maneb, mancozeb, iprodione, imazalil, chlorpyrifos ethyl, diazinon and dimethoate), as determined by the European Food Safety Authority, were selected. Their in vitro effects at low-doses on primary BM-MSCs from healthy volunteers were examined. (3) Results: Exposure of normal BM-MSCs to pesticides for 21 days inhibited cell proliferation and promoted DNA damage and senescence. Concomitantly, these cells presented a decrease in aldehyde dehydrogenase 2 (ALDH2: mRNA, protein and enzymatic activity) and an increase in acetaldehyde levels. Pharmacological inhibition of ALDH2 with disulfiram recapitulated the alterations induced by exposure to low doses of pesticides. Moreover, BM-MSCs capacity to support primitive hematopoiesis was significantly altered. Similar biological abnormalities were found in primary BM-MSCs derived from MDS patients. (4) Conclusions: these results suggest that ALDH2 could participate in the pathophysiology of MDS in elderly people long exposed to low doses of pesticides. [ABSTRACT FROM AUTHOR]

Simple Summary: A substantial fraction of the elderly population suffers from moderate anemia, and blood smear analysis can guide towards a diagnosis of myelodysplastic syndrome (MDS). Nevertheless, in medical laboratories, blood smear review is only performed when quantitative or qualitative flags occur upon complete blood count (CBC). Consequently, the suspicion of MDS can be delayed in the absence of systematic blood smear observation, which is crucial to initiate a full diagnosis process by cytological analysis of bone marrow aspiration. The Beckman Coulter DxH 800 hematology analyzer (Beckman-Coulter, Brea, CA) is widely used over the world. We propose in this study the clinical use of 10 unexploited "research parameters" for early detection of subclinical MDS by selective triggering of blood smear examination. The incidence of myelodysplastic syndrome increases with aging and the early diagnosis enables optimal care of these diseases. The DxH 800 hematology analyzer measures and calculates 126 cytological parameters, but only 23 are used for routine CBC assessment. The goal of this study was to use the 103 unexploited "research parameters" to develop an algorithm allowing for an early detection of subclinical MDS patients by triggering morphological analysis. Blood sample parameters from 101 MDS patients and 88 healthy volunteers were analyzed to identify the critical "research parameters" with: (i) the most significant differences between MDS patients and healthy volunteers, (ii) the best contributions to principal component analysis (PCA), first axis, and (iii) the best correlations with PCA, first two axes (cos2 > 0.6). Ten critical "research parameters" of white blood cells were identified, allowing for the calculation of an MDS-likelihood score (MDS-LS), based on logistic regression. Automatic calculation of the MDS-LS is easily implementable on the middleware system of the DxH 800 to generate a flag for blood smear review, and possibly early detection of MDS patients in the general population. [ABSTRACT FROM AUTHOR]