Epigenetic control of T helper cells differentiation: a mechanistic insight into the association between acute leukemia and coronary artery disease.

Even with today's sophisticated medical procedures, the two top causes of death worldwide continue to be cancer and coronary artery disease (CAD). Compared to patients with other malignancies, people with acute leukemia (AL) have a higher incidence of congestive heart failure. It is yet unknown how recently discovered AL and CAD are related. Recent research highlights P53's critical role as a "gatekeeper" of cardiac function, facilitating the repair of double-strand DNA breaks. Mutations in TP53 lead to impaired DNA repair, increased cardiomyocyte apoptosis following ischemia, and ultimately contribute to cardiac dysfunction. The current study aims to investigate epigenetic regulators' role in CD4+ T helper cells (TH) extracted from Peripheral Blood Mononuclear Cells (PBMCs) of Coronary Artery Disease (CAD) and Acute Leukemia (AL) patients, potentially elucidating their connection. Our experimental data revealed that reduced P53 gene expression correlated with increased Histone (H3) trimethylation on Lysine residue 27 (K27), DNA methylation, and R-loop frequencies, alongside decreased Histone (H3) trimethylation on Lysine residue 4 (K4) and m6A methylation, contributing to diminished TH1-ness in CAD and AL patients. Through P53 depletion and overexpression in CD4+TH cells of Normal subjects, CAD, and AL patients, we observed that P53 overexpression reversed these epigenetic and epitranscriptomic modifications. Specifically, in immunologically challenged CD4+TH cells of CAD and AL patients, P53 overexpression led to decreased K27 trimethylation, DNA methylation, and R-loop frequencies, coupled with increased K4 trimethylation and m6A methylation, subsequently upregulating mRNA levels of TH1-associated genes, promoting protective immunity. Therefore, a thorough understanding of the intricate relationship between CAD and AL may improve prevention, prompt detection, and appropriate treatment of those diseases.