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JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

ABSTRACT: JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

PROVIDER: PRJNA492885 | ENA |

REPOSITORIES: ENA

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JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

Project description:Pegylated interferon-alpha (peg-IFNa) treatment induces molecular remissions (MR) in patients with myeloproliferative neoplasms (MPN), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F vs. CALR-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p=0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of interferon-stimulated genes in JAK2V617F-positive 32D cells compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F mutant 32D cells.

2018-10-29 | GSE120363 | GEO

Gene expression data from CD34+ BMMCs/PBMCs from JAK2V617F positive and CALR mutated MPN patients

Project description:Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET) In this dataset, we compare the gene expression data of patients JAK2V617F vs. CALR-mutated MPN patients.

2018-10-29 | GSE120362 | GEO

Gene and miRNA expression profiles in Polycythemia Vera and Essential Thrombocythemia according to CALR and JAK2 mutations [GEP]

Project description:Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50–70% of ET patients harbour the V617F mutation in the exon 14 of JAK2 gene, while about 20-30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CARL-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here we showed that CALR-mutated and JAK2V617F-positive CD34+ cells have different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e. mTOR, MAPK/PI3K and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodelling, splicing and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the down-regulation of several genes involved in thrombin signalling and platelet activation. As a whole, these data support the model in which CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients.

2018-03-01 | GSE103237 | GEO

Gene and miRNA expression profiles in Polycythemia Vera and Essential Thrombocythemia according to CALR and JAK2 mutations [miEP]

2018-03-01 | GSE103238 | GEO

The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network

Project description:Background and Aims: The LIM protein AJUBA participates in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription, yet its roles in tumor development and progression are poorly defined. The aim is to determine the role of AJUBA in colorectal tumorigenesis. Methods: We performed data mining in Oncomine databases and immunohistochemistry (IHC) assays on 67 paired colorectal cancer (CRC) samples; we manipulated the AJUBA expression in SW-1116 and Caco-2 cells using specific shRNA and overexpression plasmids and performed assays for cell viability, cell cycle and apoptosis; we performed RNA-seq and qRT-PCR assays to identify genes regulated by AJUBA; we performed western blot, co-immunoprecipitation assays to study the interaction of AJUBA and JAK/STAT; Results: We discovered that AJUBA is highly expressed in CRC and promotes CRC cell growth in culture and in xenograted mice via an inhibition of apoptosis by repression of the IFIT2 gene. AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulted in inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Conclusion: Ajuba functions as a specific suppressor of the Interferon-activated JAK1/STAT1 signaling to promote colorectal cancer development via an inhibition of Interferon induced apoptosis.

2017-02-23 | GSE84902 | GEO

Gene expression data from CD34+ BMMCs/PBMCs from JAK2V617F positive and CALR mutated MPN patients

Project description:Gene expression data from CD34+ BMMCs/PBMCs from JAK2V617F positive and CALR mutated MPN patients

| PRJNA492886 | ENA

Triple negative, JAK2V617F and CALR mutated essential thrombocythaemia patients share a unique gene expression signature

Project description:Triple negative, JAK2V617F and CALR mutated essential thrombocythaemia patients share a unique gene expression signature

| PRJNA658320 | ENA

Profiling of transcriptional targets of Jak1 and Stat1 in proliferating and differentiating myoblasts

Project description:Profiling of transcriptional targets of Jak1 and Stat1 in proliferating and differentiating myoblasts

| PRJNA1090896 | ENA

CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response

Project description:Cancer is driven by somatic mutations that provide a fitness advantage. While targeted therapies often focus on the mutated gene or its direct downstream effectors, imbalances brought on by cell-state alterations may also confer unique vulnerabilities. In myeloproliferative neoplasms (MPN), somatic mutations in the calreticulin (CALR) gene are disease-initiating through aberrant binding of mutant CALR to the thrombopoietin receptor MPL and ligand-independent activation of JAK-STAT signaling. Despite these mechanistic insights into the pathogenesis of CALR-mutant MPN, there are currently no mutant CALR-selective therapies available. Here, we identified differential upregulation of unfolded and ubiquitinylated proteins, the proteasome and the ER stress response in CALR-mutant hematopoietic stem cells and megakaryocyte progenitors. We further found that combined pharmacological inhibition of the proteasome and IRE1-XBP1 axis of the ER stress response preferentially targets Calr-mutated stem and progenitors over wild-type cells in vivo, resulting in an amelioration in the MPN phenotype. Together, these findings leverage loss of proteostasis in Calr-mutant MPN to identify combinatorial dependencies that may be targeted for therapeutic benefit.

2023-10-12 | GSE207684 | GEO

Triple negative, JAK2V617F and CALR mutated essential thrombocythaemia patients share a unique gene expression signature [array]

Project description:Triple negative, JAK2V617F and CALR mutated essential thrombocythaemia patients share a unique gene expression signature [array]

| PRJNA658325 | ENA

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