Activation of CaMKIIγ potentiates T-cell acute lymphoblastic leukemia leukemogenesis via phosphorylating FOXO3a.

Ca2+/calmodulin-dependent protein kinase II γ (CaMKIIγ) can regulate the proliferation and differentiation of myeloid leukemia cells and accelerate chronic myeloid leukemia blast crisis, but the role of CaMKIIγ in T-cell acute lymphoblastic leukemia (T-ALL) leukemogenesis remains poorly understood. We observed that activated (autophosphorylated) CaMKIIγ was invariably present in T-ALL cell lines and in the majority of primary T-ALL samples. Overexpression of CaMKIIγ enhanced the proliferation, colony formation, in vivo tumorigenesis and increased DNA damage of T-ALL leukemia cells. Furthermore, inhibition of CaMKIIγ activity with a pharmacologic inhibitor, gene knock-out, dominant-negative constructs or enhancement of CaMKIIγ activity by overexpression constructs revealed that the activated CaMKIIγ could phosphorylate FOXO3a. In Jurkat cells, the activated CaMKIIγ phosphorylated FOXO3a via directly or indirectly phosphorylating AKT, excluded FOXO3a from the nucleus and inhibited its transcriptional activity. These results indicate that the activated CaMKIIγ may play a key role in T-ALL leukemogenesis, and targeting CaMKIIγ might be a value approach in the treatment of T-ALL.

Bile acid signaling and bariatric surgery.

The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications. Bariatric surgical procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), currently provide the most effective treatment for obesity and type 2 diabetes (T2D), as well as for non-alcoholic steatohepatitis (NASH). However, the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive. Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery. This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5) in bariatric surgery. We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.