Molecular Oncology (Jun 2024)

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

  • Stefan Djordjevic,
  • Raphaël Itzykson,
  • Frédéric Hague,
  • Delphine Lebon,
  • Julien Legrand,
  • Hakim Ouled‐Haddou,
  • Guillaume Jedraszak,
  • Juliette Harbonnier,
  • Louison Collet,
  • Etienne Paubelle,
  • Jean‐Pierre Marolleau,
  • Loïc Garçon,
  • Thomas Boyer

DOI
https://doi.org/10.1002/1878-0261.13584
Journal volume & issue
Vol. 18, no. 6
pp. 1571 – 1592

Abstract

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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.

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