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

• Main Authors: Shella Saint Fleur-Lominy, Mate Maus, Martin Vaeth, Ingo Lange, Isabelle Zee, David Suh, Cynthia Liu, Xiaojun Wu, Anastasia Tikhonova, Iannis Aifantis, Stefan Feske
• Format: Article
• Language: English
• Published: Elsevier 2018-09-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718313019

Summary: 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. Keywords: T cell acute lymphoblastic leukemia, T-ALL, Notch1, STIM1, STIM2, calcium, Ca2+, CRAC channel, inflammation, interferon, anemia, macrophages