STIM2 is involved in the regulation of apoptosis and cell cycle in normal and malignant monocytic cells

Abstract

Abstract Background Calcium is a ubiquitous messenger that regulates a wide range of cellular functions including proliferation, cell migration and apoptosis. Abnormal expression of proteins involved in Ca2+ signaling has been associated with oncogenesis in many solid tumor models. However, its involvement in the pathophysiology of acute myeloid leukemia is less investigated. In this work, we aimed to identify actors of Ca2+ signaling involved in leukemogenesis. Methods From an analysis of TCGA and GTEx databases, we identified STIM2, a key sensor regulating Ca2+ capacitive entry, as highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients, showing an association of a high STIM2 expression with adverse risk group according to ELN17 classification. We then investigated the role of STIM2 in cell proliferation, differentiation and survival by modulating its expression in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells driven into monocytic differentiation. Results STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double-strand breaks, as shown by increased p-H2AXγ, followed by activation of the p53 pathway, decreased expression of cell cycle regulators such as CDK1-cyclin B1 and the CDC25c phosphatase, and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. This phenotype was not observed in two p53-deleted cell lines, HL60 and K562. Using a model of in vitro monocytic differentiation of peripheral blood-derived CD34+ cells, we observed higher STIM2 expression at the RNA level in differentiated cells. The acquisition of monocytic markers was faster after STIM2 forced expression, while STIM2 knockdown impaired CD14 expression and led to p-H2AXγ, p53 induction, apoptosis and cell cycle blockage, in agreement with data observed in leukemic cell lines. Conclusions In summary, we report STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells. Considering the association of high STIM2 expression with an adverse prognosis in AML and the association of STIM2 with AML harboring monocytic/myelomonocytic differentiation.