ArticleBlood cancer discovery2022
Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms.
Article in Blood cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 33 citations in OpenAlex.
- The Effects of Disrupting CaMarine biotechnology (New York, N.Y.) · 2026Article
- RBM39 modulates UPR signaling through alternative splicing of IRE1α/Genes & development · 2026Article
- Calreticulin Type 26 Mutation in Myelofibrosis: A Rare Variant With Diagnostic Challenges.Journal of clinical laboratory analysis · 2026Article
- Mutant calreticulin-Cancer driver and Achilles' heel for ET?HemaSphere · 2026Article
- Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis.Blood · 2026Review
- Calcium-mediated calreticulin-IRE1α interaction drives dynamic fluctuation of IRE1α activity under chronic endoplasmic reticulum stress.Nature communications · 2026Article
- CALR accelerates the growth of liver cancer cells by enhancing telomere activity via ARAF.Genes & diseases · 2026Article
- Molecular and Functional Analysis of Calcium Binding by a Cancer-linked Calreticulin Mutant.bioRxiv : the preprint server for biology · 2025Article
- CALR Type 1-Like Mutations Increase Endoplasmic Reticulum Free CaCell biology international · 2025Article
- Article
- Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms.Cancers · 2025Review
- Predicting high-risk clinical missense variants of SMARCB1 in rare neurogenetic disorder schwannomatosis (nerve tumor) through sequence, structure, and molecular dynamics analyses.Neurogenetics · 2025Article
- Calreticulin-From the Endoplasmic Reticulum to the Plasma Membrane-Adventures of a Wandering Protein.Cancers · 2025Review
- Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications.Current hematologic malignancy reports · 2025Review
- Myeloproliferative Neoplasm-like Mutations of Calreticulin Induce Phenotypes Associated with Calreticulin Dysfunction inInternational journal of molecular sciences · 2024Article
- The Role of Mutated Calreticulin in the Pathogenesis ofInternational journal of molecular sciences · 2024Article
- Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia.Journal of hematology & oncology · 2024Article
- Review
- NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.Molecular cancer research : MCR · 2024Article
- Type 1 CALR mutation allele frequency correlates with CD34/CXCR4 expression in myelofibrosis-type megakaryocyte dysplasia: A mechanism of disease progression?Blood cancer journal · 2024Article
Corrections and comments
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Authors and funding
28 authors at 7 institutions in 4 countries.
Funding
Abstract
Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2+ binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo. SIGNIFICANCE: Current targeted therapies for CALR-mutated MPNs are not curative and fail to differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs. This article is highlighted in the In This Issue feature, p. 265.
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