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

• Published in: Molecular oncology 2024-06, Vol.18 (6), p.1571-1592
• Main Authors: Djordjevic, Stefan, Itzykson, Raphaël, Hague, Frédéric, Lebon, Delphine, Legrand, Julien, Ouled‐Haddou, Hakim, Jedraszak, Guillaume, Harbonnier, Juliette, Collet, Louison, Paubelle, Etienne, Marolleau, Jean‐Pierre, Garçon, Loïc, Boyer, Thomas
• Format: Article
• Language: English
• Subjects: Acute Myeloid Leukemia; Apoptosis; Apoptosis - genetics; Bone marrow; calcium; Cancer; Cell cycle; Cell Cycle - genetics; Cell Differentiation; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell survival; Cyclin B1; Cytokines; DNA damage; Endoplasmic reticulum; Female; Flow cytometry; Genomes; Genomic analysis; genomic stress; Genotypes; Granulocytes; Hematology; Hematopoietic stem cells; Histones; Human health and pathology; Humans; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Life Sciences; Ligands; Male; Medical prognosis; Monocytes; Monocytes - metabolism; Monocytes - pathology; monocytic cells; p53 Protein; Penicillin; Phosphorylation; Proteins; SOCE; Stem cells; Stromal Interaction Molecule 2 - genetics; Stromal Interaction Molecule 2 - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13584

Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. 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 levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports 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. This research uncovers an important role of STIM2 in the proliferation and survival of normal and malignant monocytic cells. STIM2 knockdown in both cell type leads to decreased cell proliferation and survival through induction of genotoxic stress and induction of p53, leading to cell cycle block and apoptosis in both cell types. STIM2 may be a potential target in AML treatment.