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

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

PROVIDER: PRJNA801866 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17818700.fastq.gz	Fastqsanger.gz
	SRR17818701.fastq.gz	Fastqsanger.gz
	SRR17818702.fastq.gz	Fastqsanger.gz
	SRR17818694.fastq.gz	Fastqsanger.gz
	SRR17818695.fastq.gz	Fastqsanger.gz

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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

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.

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

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Calreticulin mutated hematopoietic cells are vulnerable to ATR-CHK1 pathway inhibition

Project description:Disease frameshift mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF). To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we aimed to search for small molecule drugs that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89,172 compounds using isogenic cell lines and identified several hits targeting the ATR-CHK1 pathway. The selective inhibitory effect of these candidate compounds was validated in a co-culture assay of CALR mutated and wild type cells. Of the tested hit compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing CALR wild type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to the drug treatment, suggesting that the vulnerability to ATR-CHK1 inhibition is specifically caused by the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. They also promoted S-phase cell cycle arrest and blocked the completion of DNA replication in CALR mutated cells. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by the oncogenic CALR mutation, suggesting an intrinsic vulnerability of these cells to CHK1 perturbation. This study indicates that ATR-CHK1 pathway is a potential therapeutic target in CALR mutated hematopoietic cells.

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