STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia

Shella Saint Fleur-Lominy, Mate Maus, Martin Vaeth, Ingo Lange, Isabelle Zee, David Suh, Cynthia Liu, Xiaojun Wu, Anastasia Tikhonova, Iannis Aifantis, Stefan Feske

Research output: Contribution to journalArticle

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of T cell progenitors affecting children and adults. Saint Fleur-Lominy et al. show that calcium influx mediated by STIM1 and STIM2 promotes the proinflammatory function of leukemic cells and premature death from leukemia.

Original languageEnglish (US)
Pages (from-to)3045-3060.e5
JournalCell Reports
Volume24
Issue number11
DOIs
StatePublished - Sep 11 2018

Keywords

  • CRAC channel
  • Ca
  • Notch1
  • STIM1
  • STIM2
  • T cell acute lymphoblastic leukemia
  • T-ALL
  • anemia
  • calcium
  • inflammation
  • interferon
  • macrophages

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Saint Fleur-Lominy, S., Maus, M., Vaeth, M., Lange, I., Zee, I., Suh, D., Liu, C., Wu, X., Tikhonova, A., Aifantis, I., & Feske, S. (2018). STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia. Cell Reports, 24(11), 3045-3060.e5. https://doi.org/10.1016/j.celrep.2018.08.030