STIM1 and STIM2 mediate cancer-induced inflammation in T cell acute lymphoblastic leukemia
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ABSTRACT:
PROVIDER: PRJNA480224 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7499333_1.fastq.gz | Fastqsanger.gz | |||
| SRR7499333_2.fastq.gz | Fastqsanger.gz | |||
| SRR7499334_1.fastq.gz | Fastqsanger.gz | |||
| SRR7499334_2.fastq.gz | Fastqsanger.gz | |||
| SRR7499335_1.fastq.gz | Fastqsanger.gz |
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of T cell progenitors that in most patients is associated with activating mutations in the NOTCH1 pathway. Recent reports have indicated a link between Ca2+ homeostasis in the endoplasmic reticulum (ER), the regulation of NOTCH1 signaling and T-ALL. Here we investigated the role of store-operated Ca2+ entry (SOCE) in T-ALL. SOCE is a Ca2+ influx pathway that is mediated by the plasma membrane Ca2+ channel ORAI1 and its activators STIM1 and STIM2. Deletion of STIM1 and STIM2 in leukemic cells abolished SOCE and significantly prolonged the survival of mice in a NOTCH1-driven model of T-ALL. The survival advantage was unrelated to leukemia development and leukemic cell burden, but was associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with wildtype T-ALL showed a severe necroinflammatory response in their bone marrow, which was absent in mice with Stim1/2-/- leukemia. Several signaling pathways previously linked to cancer-induced inflammation were downregulated in Stim1/2-/- leukemic cells, likely accounting for less aggressive leukemia progression and prolonged survival of mice. Our study shows that T-ALL is associated with inflammation of leukemia-infiltrated organs and that SOCE controls the proinflammatory effects of leukemic T lymphoblasts.
2018-07-11 | GSE116776 | GEO
Project description: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.
| S-EPMC6170166 | biostudies-literature
Project description:Stromal interaction molecules (STIMs) are endoplasmic reticulum resident proteins that regulate Ca2+ homeostasis and signaling by store-operated calcium entry (SOCE). The different properties and functions of STIM1 and STIM2 have been described mostly based on work in vitro. Since STIM2 knockout mice do not survive till the adulthood we generated stim2a and stim2b double knockout zebrafish and characterized it. This (stim2a;stim2b)-/- fish were fertile and did not have apparent morphological phenotype. However, RNA-sequencing revealed 1424 genes differentially expressed with at least 2-fold change. One of the most upregulated gene was annexinA3a, which is a marker of activated microglia. This corresponded well to augmented Neutral Red staining observed by imaging in vivo of (stim2a;stim2b)-/- brain. The lack of Stim2 decreased survival of fish under low oxygen conditions. Behavioral tests such as visual-motor response and dark-light preferences indicated that (stim2a;stim2b)-/- larvae might have problems with vision. This is consistent with GO BP's analysis, which showed downregulation of many genes related to light perception. The Periodic acid-Schiff staining of retina sections from adult fish reveled the alteration in stratum pigmentosum suggesting involvement of Stim2-dependent process in visual perception. Together, these data reveal new functions for Stim2 in nervous system.
2024-12-31 | GSE219273 | GEO
Project description:RNA-Seq Analysis of SH-SY5Y or HEK293 cells with genetic modification to delete STIM2 or STIM1 and STIM2
| PRJEB60562 | ENA
Project description:Influence of STIM1 on the transcriptome of CD4+ T cell subsets STIM1 is critical for the regulation of the intracellular Ca2+ homeostasis in CD4+ T cell. Loss of function mutations in STIM1 in patients result in severe immuno deficiency and recurrent infections. Using conditional knock out mice for STIM1, we investigated the role of STIM1 in T cells during chronic infections by in-vivo and in-vitro experiments. We found that STIM1 is required for T cell-mediated immunity to chronic infection with Mycobacterium tuberculosis (Mtb) as STIM1-deficient mice succumb to infection faster than littermate controls, have increased mycobacterial burdens and severe pulmonary infiltration with myeloid and lymphoid cells .Using the Affymetrix Mouse Exon 1.0 platform, we analyzed the influence of STIM1 expression on the transcriptom of CD4+T cells in-vitro. We found that STIM1 is required for the regulation of apoptosis related genes after TCR stimulation as well as for the induction of a transcriptonal program that polarizes naive CD4+ T cells into inducible CD4+ T regulatory cells (iTreg). Together with our in-vivo findings, these experiments reveal that STIM1 is essential for immune regulation to prevent an injurious inflammatory response during chronic infection.
2015-03-17 | GSE66933 | GEO
Project description:Sjogren’s Disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, and extra glandular manifestations. The etiology and pathophysiology of SjD are incompletely understood. Regulatory T (Treg) cells are critical for immunological tolerance and although Treg abnormalities have been implicated in the pathogenesis of several autoimmune diseases, their role in SjD remains ambiguous. We here show that Stim1fl/flStim2fl/flFoxp3-Cre (Stim1/Stim2 Foxp3cre) mice develop a SjD-like phenotype, including severe sialadenitis with hyposalivation, lacrimal gland (LG) inflammation with dry eye and corneal damage, increased anti-Ro and anti-La autoantibody levels and interstitial lung disease. At the cellular level, salivary gland inflammation in Stim1/2Foxp3 mice is characterized by infiltration with CD4+ and CD8+ T cells, which is dominated by a T helper (Th) 1 and Th2 immune response. The changes in gene expression in SGs of mice correlate strongly with transcriptional and epigenetic dysregulation found in SjD patients. Our findings in Stim1/Stim2 Foxp3cre mice provide new evidence for a critical role of Treg cells and IFNγ producing Th1 cells in mediating SjD progression.
2024-11-04 | GSE253188 | GEO
Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.
2016-03-10 | E-GEOD-79039 | biostudies-arrayexpress
Project description:Phenotype of stim2 zebrafish knockout
| PRJNA907845 | ENA
Project description:DNA damage represents a challenge for cells as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or eliminate unscheduled chemical modifications in genomic DNA, an extensive signaling network, known as the DNA damage response (DDR) pathway, ensures this repair. In this work, and by means of a proteomic analysis aimed at the study of the STIM1 protein interactome, we have found that STIM1 is closely related to the protection from endogenous DNA damage, replicative stress, as well as in the response to interstrand crosslinks (ICLs). Here we show that STIM1 has a nuclear localization signal (NLS) that mediates its translocation to the nucleus, and that this translocation and the association of STIM1 to chromatin is enhanced in response to mitomycin C (MMC), an ICL-inducing agent. Consequently, STIM1-deficient cell lines show a higher level of basal DNA damage, replicative stress, and a higher sensitivity to MMC. We show that STIM1 normalizes FANCD2 protein levels in the nucleus, explaining the increased sensitivity to MMC in STIM1-KO cells. Our results show for the first time a nuclear function for the endoplasmic reticulum protein STIM1 and increase the number of genes involved in DNA repair.
2023-12-22 | PXD041181 | Pride
Project description:To investigate the altered glucose and lipid metabolism genes after STIM1 knockout (STIM1 KO) or STIM1 knockout plus Snail1 OE (STIM1 KO+Snail1 OE) in SMMC7721 cells. STIM1 KO-SMMC7721 cells were constructed by CRISPR/Cas9, and STIM1 KO+Snail1 OE-SMMC7721 cells was established via lentiviral Infection of Snail1 overexpression in STIM1 KO-SMMC7721 cells. The cells mentioned above were cultured in DMEM supplemented with 10% (v/v) FBS at 37 °C in 5% CO2. When the cells grow to 60~70% confluent, total RNA was extracted by using Trizol (TAKARA, Japan). Reverse transcription was performed from 1μg total RNA using PrimeScript™ RT reagent Kit with gDNA Eraser (TAKARA), Quantitative real-time PCR were performed (CFX386, BioRad) with 40 cycles at 95 °C for 10 seconds, 59 °C for 20 seconds and 72 °C for 30 seconds.
2020-04-07 | GSE148129 | GEO