TY  - JOUR
A1  - Saint Fleur-Lominy, Shella
A1  - Maus, Mate
A1  - Vaeth, Martin
A1  - Lange, Ingo
A1  - Zee, Isabelle
A1  - Suh, David
A1  - Liu, Cynthia
A1  - Wu, Xiaojun
A1  - Tikhonova, Anastasia
A1  - Aifantis, Iannis
A1  - Feske, Stefan
T1  - STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia
JF  - Cell Reports
N2  - 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.
KW  - T cell acute lymphoblastic leukemia
KW  - T-ALL
KW  - Notch1
KW  - STIM1
KW  - STIM2
KW  - calcium
KW  - Ca2+
KW  - CRAC
KW  - channel
KW  - inflammation
KW  - interferon
KW  - anemia
KW  - macrophages
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227259
VL  - 24
IS  - 11
ER  - 
TY  - JOUR
A1  - Vaeth, Martin
A1  - Wang, Yin-Hu
A1  - Eckstein, Miriam
A1  - Yang, Jun
A1  - Silverman, Gregg J.
A1  - Lacruz, Rodrigo S.
A1  - Kannan, Kasthuri
A1  - Feske, Stefan
T1  - Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels
JF  - Nature Communications
N2  - T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.
KW  - gene regulation in immune cells
KW  - lymphocytes
KW  - regulatory T cells
KW  - signal transduction
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232148
VL  - 10
ER  -