Alterations of the expression of TET2 and DNA 5-hmC predict poor prognosis in Myelodysplastic Neoplasms.

BACKGROUND: Myelodysplastic Neoplasms (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis and progression to acute myeloid leukemia, myelodysplasia-related (AML-MR). A major mechanism of pathogenesis of MDS is the aberration of the epigenetic landscape of the hematopoietic stem cells and/or progenitor cells, especially DNA cytosine methylation, and demethylation. Data on TET2, the predominant DNA demethylator of the hematopoietic system, is limited, particularly in the MDS patients from India, whose biology may differ since these patients present at a relatively younger age. We studied the expression and the variants of TET2 in Indian MDS and AML-MR patients and their effects on 5-hydroxymethyl cytosine (5-hmC, a product of TET2 catalysis) and on the prognosis of MDS patients. RESULTS: Of the 42 MDS patients, cytogenetics was available for 31 sub-categorized according to the Revised International Prognostic Scoring System (IPSS-R). Their age resembled that of the previous studies from India. Bone marrow nucleated cells (BMNCs) were also obtained from 13 patients with AML-MR, 26 patients with de-novo AML, and 11 subjects with morphologically normal bone marrow. The patients had a significantly lower TET2 expression which was more pronounced in AML-MR and the IPSS-R higher-risk MDS categories. The 5-hmC levels in higher-risk MDS and AML-MR correlated with TET2 expression, suggesting a possible mechanistic role in the loss of TET2 expression. The findings on TET2 and 5-hmC were also confirmed at the tissue level using immunohistochemistry. Pathogenic variants of TET2 were found in 7 of 24 patient samples (29%), spanning across the IPSS-R prognostic categories. One of the variants - H1778R - was found to affect local and global TET2 structure when studied using structural predictions and molecular dynamics simulations. Thus, it is plausible that some pathogenic variants in TET2 can compromise the structure of TET2 and hence in the formation of 5-hmC. CONCLUSIONS: IPSS-R higher-risk MDS categories and AML-MR showed a reduction in TET2 expression, which was not apparent in lower-risk MDS. DNA 5-hmC levels followed a similar pattern. Overall, a decreased TET2 expression and a low DNA 5-hmC level are predictors of advanced disease and adverse outcome in MDS in the population studied, i.e., MDS patients from India.

Potential SARS-CoV-2 interactions with proteins involved in trophoblast functions - An in-silico study.

BACKGROUND: Though a large number of pregnant females have been affected by COVID-19, there is a dearth of information on the effects of SARS-CoV-2 infection on trophoblast function. We explored in silico, the potential interactions between SARS-CoV-2 proteins and proteins involved in the key functions of placenta. METHODS: Human proteins interacting with SARS-CoV-2 proteins were identified by Gordon et al. (2020). Genes that are upregulated in trophoblast sub-types and stages were obtained by gene-expression data from NCBI-GEO and by text-mining. Genes altered in pathological states like pre-eclampsia and gestational diabetes mellitus were also identified. Genes crucial in placental functions thus identified were compared to the SARS-CoV-2 interactome for overlaps. Proteins recurring across multiple study scenarios were analyzed using text mining and network analysis for their biological functions. RESULTS: The entry receptors for SARS-CoV-2 - ACE2 and TMPRSS2 are expressed in placenta. Other proteins that interact with SARS-CoV-2 like LOX, Fibulins-2 and 5, NUP98, GDF15, RBX1, CUL3, HMOX1, PLAT, MFGE8, and MRPs are vital in placental functions like trophoblast invasion and migration, syncytium formation, differentiation, and implantation. TLE3, expressed across first trimester placental tissues and cell lines, is involved in formation of placental vasculature, and is important in SARS-CoV (2003) budding and exit from the cells by COPI vesicles. CONCLUSION: SARS-CoV-2 can potentially interact with proteins having crucial roles in the placental function. Whether these potential interactions identified in silico have effects on trophoblast functions in biological settings needs to be addressed by further in vitro and clinical studies.