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

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

PROVIDER: PRJNA756365 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15530485_1.fastq.gz	Fastqsanger.gz
	SRR15530485_2.fastq.gz	Fastqsanger.gz
	SRR15530486_1.fastq.gz	Fastqsanger.gz
	SRR15530486_2.fastq.gz	Fastqsanger.gz
	SRR15530487_1.fastq.gz	Fastqsanger.gz

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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

CALR frameshift mutations in MPN patient-derived iPSCs accelerate maturation of megakaryocytes.

Project description:Calreticulin (CALR) mutations are driver mutations in myeloproliferative neoplasms (MPNs), leading to activation of the thrombopoietin receptor and causing abnormal megakaryopoiesis. Here, we generated patient-derived CALRins5- or CALRdel52-positive induced pluripotent stem cells (iPSCs) to establish an MPN disease model for molecular and mechanistic studies. We demonstrated myeloperoxidase deficiency in granulocytic cells derived from homozygous CALR mutant iPSCs, rescued by repairing the mutation using CRISPR/Cas9. iPSC-derived megakaryocytes showed characteristics of primary megakaryocytes such as formation of demarcation membrane system and cytoplasmic pro-platelet protrusions. Importantly, CALR mutations led to enhanced megakaryopoiesis and accelerated megakaryocytic development in a thrombopoietin-independent manner. Mechanistically, our study identified differentially regulated pathways in mutated versus unmutated megakaryocytes, such as hypoxia signaling, which represents a potential target for therapeutic intervention. Altogether, we demonstrate key aspects of mutated CALR-driven pathogenesis dependent on its zygosity, and found novel therapeutic targets, making our model a valuable tool for clinical drug screening in MPNs.

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Whole-genome CRISPR screening identifies N-glycosylation as an essential pathway and a potential novel therapeutic target in CALR-mutant MPN (Pooled CRISPR Screen).

Project description:Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPN). Although the biological mechanism by which CALR mutations cause MPN has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPN. To identify unique genetic dependencies in CALR-mutant MPN, we performed a whole-genome CRISPR knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (amongst others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells in vitro. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor, 2-deoxy-glucose (2-DG), and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared to wild-type cells, and a normalization of key MPN disease features. These findings advance the development of clonally selective treatments for CALR-mutant MPN.

2022-09-21 | GSE203455 | GEO

Whole-genome CRISPR screening identifies N-glycosylation as an essential pathway and a potential novel therapeutic target in CALR-mutant MPN (Whole Genome CRISPR Screen).

2022-09-21 | GSE203456 | 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

Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis [MPN patients]

Project description:We used expression profiling, SNP arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in all MPN patients regardless of clinical phenotype or mutational status. In addition, the activated JAK2 signature was present in patients with somatic CALR mutations. Conversely, we identified a gene expression signature of CALR mutations; this signature was significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK mutational status are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis. [MPN patients] We have performed microarray gene expression analysis in 93 patients with MPNs (28 PV, 47 ET, 18 MF) and 11 age-matched normal donors.

2014-06-03 | E-GEOD-54644 | biostudies-arrayexpress

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-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

Oncogenic CALR Mutant C-terminus Mediates Dual Binding to the Thrombopoietin Receptor Triggering Complex Dimerization and Activation

Project description:Calreticulin (CALR) is a master lectin chaperone that guides the proper folding of integral membrane proteins in the endoplasmic reticulum. In healthy cells, CALR transiently and non-specifically interacts with thousands of immature N-glycosylated proteins through its N-terminal glycan-binding domain. Conversely, frameshift mutants of CALR turn into rogue cytokine by acquiring the ability to stably and specifically interact with the Thrombopoietin Receptor (TpoR). Strikingly, this interaction induces activation of TpoR leading to myeloproliferative neoplasms, blood cancers resulting from the overproduction of blood cells. Using a multidisciplinary approach, we unveil how the CALR frameshift mutations result in structural overhaul of the entire protein and identify the structural basis of its acquired specificty for TpoR. We further describe the mechanisms by zhich complex formation triggers TpoR dimerization and activation. In addition, we provide the first complete dynamic conformational footprints of both wild-type and mutant CALR and identify novel potentially targetable sites.

2023-04-11 | PXD034131 | Pride

Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis [MPN patients]

2014-06-03 | GSE54644 | GEO