Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

Photographic appraisal of crystal lattice growth technique.

Concept of creating mechanical retention for bonding through crystal growth has been successfully achieved in the present study. By using polyacrylic acid, sulphated with sulphuric acid as etchant, abundant crystal growth was demonstrated. Keeping in view the obvious benefits of crystal growth technique, the present SEM study was aimed to observe and compare the changes brought about by different etching agents (phosphoric acid, polyacrylic acid and polyacrylic acid sulphated) and to evaluate their advantages and disadvantages in an attempt to reduce iatrogenic trauma caused due to surface enamel alteration. Control and experimental groups were made of 24 and 30 premolars, respectively, for scanning electron microscopic appraisal of normal unetched and etched enamel surface and fracture site and finished surface evaluation. When compared with conventional phosphoric acid and weaker polyacrylic acid, investigations indicated that crystal growth treatment on enamel surface caused minimal iatrogenic trauma and surface alteration were restored to the original untreated condition to a large extent.