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RNA-seq analysis of Calreticulin(Calr) knockout LLC cells identified ER stress response

ABSTRACT: To investigate the mechanisms by which Calreticulin inactivation increases tumor sensitivity to T cell-mediated anti-tumor immunity, LLC cells were transduced with sgRNA targeting Calreticulin or a control sgRNA, and transcriptome changes were profiled using paired-end RNA-seq. Our data demonstrated that Calr KO induces an ER stress response.

ORGANISM(S): Mus musculus

PROVIDER: GSE285113 | GEO | 2025/03/18

REPOSITORIES: GEO

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RNA-seq analysis of Calreticulin(Calr) knockout LLC cells identified ER stress response

Project description:RNA-seq analysis of Calreticulin(Calr) knockout LLC cells identified ER stress response

| PRJNA1201200 | ENA

Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants.

Project description:Somatic mutations of calreticulin (CALR) have been described in approximately 30-40% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven't been fully unraveled. In this study, we showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response (UPR). Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, leading to increase oxidative DNA damage. We finally demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. Altogether, our data identify novel mechanisms collaborating with MPL activation in CALR-mediated cellular transformation. CALR mutants negatively impact on the capability of cells to respond to oxidative stress leading to genomic instability and on the ability to react to ER stress, causing resistance to UPR-induced apoptosis.

2019-08-04 | GSE127250 | GEO

Targeting the CALR Interactome in Myeloproliferative Neoplasms

Project description:Mutations in the endoplasmic reticulum (ER) chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We employed mass spectrometry proteomics to identify novel CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57 and CALR to the MPL promoter to enhance transcription. CALR 52 mutant was also found to increase genome-wide recruitment of Fli1 to the chromatin. Overall, these results show that type 1 CALR mutant modulates Fli1 cellular localization and recruitment.

2018-09-19 | GSE120134 | GEO

CALR frameshift mutations accelerate maturation of megakaryocytes in MPN patient-derived iPS cells

Project description:In this dataset, we compare the gene expression data of induced pluripotent stem (iPS) cell-derived CD61+ megakaryocytes carrying heterozygous or homozygous Calreticulin (CALR) ins5 mutations or the CALR wildtype gene.

2021-10-21 | GSE182479 | GEO

Oncogenic Calreticulin Induces Immune Escape by Stimulating TGF-β Expression and Regulatory T Cell Expansion in the Bone Marrow Microenvironment - microarray

Project description:To understand transcriptional aberrations induced by oncogenic Calreticulin (Calr) in myeloproliferative neoplasms we used a cell line – 32D, generated from the murine myeloid precursor cells, to overexpress human thrombopoietin receptor (MPL) together with human Calr. Cells expressing oncogenic Calr show increased JAK/STAT signaling independent of extrinsic stimuli like IL3.

2024-05-30 | GSE241162 | GEO

Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in hematopoietic cells

Project description:Somatic mutations of calreticulin (CALR) have been described in approximately 30-40% of JAK2 and MPL unmutated essential trombocytemia and primary myelofibrosis patients. CALR is a chaperone that localizes primarily in the endoplasmic reticulum (ER) where it is responsible for the control of proper protein folding and for the calcium retention. Recent data have demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven myeloproliferative neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven't been fully unraveled. In this study, we attempted to clarify whether CALR mutations may affect the functions of CALR in the ER under homeostatic conditions. Our results showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response, therefore allowing the accumulation of unfolded proteins and conferring resistance to ER-stress induced apoptosis. Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, reducing the ability to counteract ROS intracellular accumulation and thus leading to increase oxidative DNA damage. We finally demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by CALR mutations. Altogether, our data identify a novel MPL-independent mechanism involved in the development of MPNs mediated by CALR mutants: CALR mutations negatively impact on the capability of cells to respond to oxidative stress, and this in turn leads to increase DNA damage and genomic instability. We used microarrays to detail the change of gene expression caused by calreticulin mutations in K562 cells

2020-08-20 | GSE102900 | GEO

Physical interaction between mutant calreticulin and the thrombopoietin receptor is required for transformation of hematopoietic cells

Project description:Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN). However, the mechanism by which mutant CALR is oncogenic is unknown. Here, we demonstrate that a megakaryocytic-specific MPN phenotype is induced when mutant CALR is over-expressed in mice and that the thrombopoietin receptor, MPL is required for mutant CALR driven transformation. Whole transcriptome analysis reveals enrichment of STAT signatures in mutant CALR transformed cells and JAK2 inhibitor treatment abrogates STAT activation. Employing extensive mutagenesis-based structure-function analysis we demonstrate that the positively charged amino acids within the mutant CALR C-terminus are required for cellular transformation through facilitating physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel mechanism of cancer pathogenesis.

2016-04-14 | GSE74890 | GEO

HIF-1-regulated expression of calreticulin promotes breast tumorigenesis and progression through Wnt/β-catenin pathway activation

Project description:Calreticulin (CALR) is a multi-functional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding and cancer progression. However, the role of CALR in breast cancer is unclear. Here we report that CALR is overexpressed in breast cancer compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24-CD44+ subsets and ALDH+ subsets, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis, and enhanced chemosensitivity in vivo. Chromatinimmunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated CALR transcription in hypoxic breast cancer cells. CALR expression was correlated with Wnt/β-catenin pathway activation and an activator of Wnt/β-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALRfacilitates breast cancer progression by promoting the BCSC phenotype through Wnt/β-catenin signaling in a HIF-1-dependent manner, and suggest that CALR may represent a novel target for breast cancer therapy.

2021-11-16 | GSE181431 | GEO

Aberrant Calreticulin expression in articular cartilage of Dio2 deficient mice

Project description:Microarray-data (Illumina MouseWG-6 v2) of knee cartilage of wild-type and Dio2 -/- -mice were re-analyzed to identify differential expressed genes independent of mechanical loading conditions by forced treadmill-running. Differential expression analyses of articular cartilage of Dio2-/- (N = 9) and wild-type-mice (N = 11) while applying a cutoff threshold (P < 0.05 (FDR) and FC > |1,5|) resulted in 1 probe located in Calreticulin (Calr) that was found significantly downregulated in Dio2-/- mice. The beneficial homeostatic state of articular cartilage in Dio2-/- mice is accompanied with significant lower expression of Calr. Functional analyses further showed that upregulation of Calr expression could act as an initiator of cartilage destruction.

2016-04-27 | GSE79239 | GEO

CALR mutation-induced transcriptional changes in cord blood-derived hematopoietic stem and progenitor cells

Project description:Recurrent mutations in calreticulin (CALR) are present in 70-80% of JAK2 unmutated myeloproliferative neoplasms (MPN). Current models of CALR mutant MPNs are mainly based on cancer cell lines with ectopic overexpression or transgenic mouse models with a lack of data for primary human hematopoietic stem and progenitor cells (HSPCs) with endogenous CALR expression. Thus, we developed a CRISPR/Cas9 and AAV6-mediated knock-in approach to introduce the two most common CALR mutations (52 bp deletion, DEL; 5 bp insertion, INS) at the endogenous gene locus in human cord blood-derived HSPCs. We used these cells to investigate transcriptional changes induced upon CALR mutation acquisition in HSPCs in a prospective manner by performing RNA-sequencing 4 days after CRISPR-mediated knock-in.

2023-01-09 | GSE195705 | GEO

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