@article{9c9d3d746f6f401499d5afdd7af6ef57,
title = "STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia",
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.",
keywords = "CRAC channel, Ca, Notch1, STIM1, STIM2, T cell acute lymphoblastic leukemia, T-ALL, anemia, calcium, inflammation, interferon, macrophages",
author = "{Saint Fleur-Lominy}, Shella and Mate Maus and Martin Vaeth and Ingo Lange and Isabelle Zee and David Suh and Cynthia Liu and Xiaojun Wu and Anastasia Tikhonova and Iannis Aifantis and Stefan Feske",
note = "Funding Information: We dedicate this article to our late colleague Dr. Lawrence B. Gardner with gratitude for his support. We thank Miriam Eckstein for help with bone decalcification and the following core facilities at NYUSOM: Immune Monitoring (multiplex cytokine analysis), Histopathology (H&E and TUNEL stains), the Genome Technology Center (GTC) (RNA sequencing), and the Applied Bioinformatics Laboratory (ABL) (help with analysis of RNA-seq data). The GTC and ABL are shared resources at NYUSOM, which are partially supported by a Cancer Center Support grant ( P30CA016087 ). We thank Drs. William Carroll, George Miller, and Meike Dittmann for critically reading the manuscript. This work was funded by a Feinberg Lymphoma pilot grant (Laura and Isaac Perlmutter Cancer Center at NYUSOM) and the NIH/NIAID ( R01AI097302 ) (to S.F.); the NIH/NCI ( R01CA202025 and R01CA133379 ), a Leukemia and Lymphoma Society grant ( 6480-16 ), and a Chemotherapy Foundation grant (to I.A.); the Luciano Research Fund , the Conquer Cancer Foundation of ASCO-YIA , and a Hematology Training grant from the NIH/NHLBI ( T32HL007151-35 ) (to S.S.F.-L.); and a Young Investigator Award by the Alex{\textquoteright}s Lemonade Stand Foundation (to M.M.). NYUSOM core facilities are supported, in part, by grants from the NIH/ORIP ( S10OD01058 and S10OD018338 ) and the National Center for Advancing Translational Sciences ( NIH/NCATS ) ( UL1 TR00038 ). Funding Information: We dedicate this article to our late colleague Dr. Lawrence B. Gardner with gratitude for his support. We thank Miriam Eckstein for help with bone decalcification and the following core facilities at NYUSOM: Immune Monitoring (multiplex cytokine analysis), Histopathology (H&E and TUNEL stains), the Genome Technology Center (GTC) (RNA sequencing), and the Applied Bioinformatics Laboratory (ABL) (help with analysis of RNA-seq data). The GTC and ABL are shared resources at NYUSOM, which are partially supported by a Cancer Center Support grant (P30CA016087). We thank Drs. William Carroll, George Miller, and Meike Dittmann for critically reading the manuscript. This work was funded by a Feinberg Lymphoma pilot grant (Laura and Isaac Perlmutter Cancer Center at NYUSOM) and the NIH/NIAID (R01AI097302) (to S.F.); the NIH/NCI (R01CA202025 and R01CA133379), a Leukemia and Lymphoma Society grant (6480-16), and a Chemotherapy Foundation grant (to I.A.); the Luciano Research Fund, the Conquer Cancer Foundation of ASCO-YIA, and a Hematology Training grant from the NIH/NHLBI (T32HL007151-35) (to S.S.F.-L.); and a Young Investigator Award by the Alex's Lemonade Stand Foundation (to M.M.). NYUSOM core facilities are supported, in part, by grants from the NIH/ORIP (S10OD01058 and S10OD018338) and the National Center for Advancing Translational Sciences (NIH/NCATS) (UL1 TR00038). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = sep,
day = "11",
doi = "10.1016/j.celrep.2018.08.030",
language = "English (US)",
volume = "24",
pages = "3045--3060.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}