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RNAseq of LSK cells from knock-in mice with Calr frameshifts

ABSTRACT: Gene expression of hematopoietic stem/progenitor cells from mice with frameshifted Calr was examined.

ORGANISM(S): Mus musculus

PROVIDER: GSE152482 | GEO | 2023/06/15

REPOSITORIES: GEO

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RNAseq of LSK cells from knock-in mice with Calr frameshifts

Project description:RNAseq of LSK cells from knock-in mice with Calr frameshifts

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Gene expression profile (GEP) of CALR-overexpressingCD34+ cells

Project description:In this work, we compared gene expression profile (GEP) of CD34+ cells transduced with the retroviral vector LCALRIDN with CD34+ cells transduced with the empty vector control LXIDN and of CD34+ cells treated with CALR siRNA with control cells transfected with a Non-Targeting siRNA In order to explore the role of CALR in the proliferation and differentiation of hematopoietic stem/progenitor cells (HPSCs), we studied the effects of CALR overexpression in Cord Blood (CB) CD34+ cells. Assessment of cell differentiation unveiled that CALR enforced expression is able to skew the haematopoietic commitment towards the MK and erythroid cell lineages. Conversely, CALR silencing induced a marked repression of MK and erythroid differentiation. In order to characterize the effects of CALR mutations on human hematopoietic cells at the molecular level, we analyzed the coding RNA profiles of CB CD34+ overexpressing CALR. This analysis identified a list of differentially expressed genes. Among upregulated genes, we found genes involved in platelet aggregation, inflammation and erythroid differentiation, potentially related to the characteristics of the disease.

2020-04-12 | GSE97807 | GEO

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

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2023-01-09 | GSE195705 | GEO

Bone marrow Mac1 and Gr1 positive cells of CALR-deficient and wild-type mice

Project description:We analyzed the effect of Calr deficiency on Mac1 and Gr1 positive bone marrow cells using hematopoietic cell specific Calr knockout (Mx-cre;Calrf/-) mice and control (Mx-cre;Calr+/+) mice.

2020-07-31 | PXD014854 | JPOST Repository

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.

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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.

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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.

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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

Clinical drug response and proteotype profiling elucidates targetable vulnerabilities of myelofibrosis

Project description:Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.

2023-10-12 | PXD036075 | Pride

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