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Cell Research Jan 2021Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca... (Review)
Review
Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca buffer to assist correct protein folding within the ER. Besides favoring the maintenance of cellular proteostasis, these cell-intrinsic CALR functions support Ca-dependent processes, such as adhesion and integrin signaling, and ensure normal antigen presentation on MHC Class I molecules. Moreover, cancer cells succumbing to immunogenic cell death (ICD) expose CALR on their surface, which promotes the uptake of cell corpses by professional phagocytes and ultimately supports the initiation of anticancer immunity. Thus, loss-of-function CALR mutations promote oncogenesis not only as they impair cellular homeostasis in healthy cells, but also as they compromise natural and therapy-driven immunosurveillance. However, the prognostic impact of total or membrane-exposed CALR levels appears to vary considerably with cancer type. For instance, while genetic CALR defects promote pre-neoplastic myeloproliferation, patients with myeloproliferative neoplasms bearing CALR mutations often experience improved overall survival as compared to patients bearing wild-type CALR. Here, we discuss the context-dependent impact of CALR on malignant transformation, tumor progression and response to cancer therapy.
Topics: Antigen Presentation; Calreticulin; Humans; Mutation; Myeloproliferative Disorders; Neoplasms; Prognosis; Signal Transduction
PubMed: 32733014
DOI: 10.1038/s41422-020-0383-9 -
Blood Apr 2023BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal diseases originating from a single hematopoietic stem cell that cause excessive production of mature... (Review)
Review
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal diseases originating from a single hematopoietic stem cell that cause excessive production of mature blood cells. The 3 subtypes, that is, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are diagnosed according to the World Health Organization (WHO) and international consensus classification (ICC) criteria. Acquired gain-of-function mutations in 1 of 3 disease driver genes (JAK2, CALR, and MPL) are the causative events that can alone initiate and promote MPN disease without requiring additional cooperating mutations. JAK2-p.V617F is present in >95% of PV patients, and also in about half of the patients with ET or PMF. ET and PMF are also caused by mutations in CALR or MPL. In ∼10% of MPN patients, those referred to as being "triple negative," none of the known driver gene mutations can be detected. The common theme between the 3 driver gene mutations and triple-negative MPN is that the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is constitutively activated. We review the recent advances in our understanding of the early events after the acquisition of a driver gene mutation. The limiting factor that determines the frequency at which MPN disease develops with a long latency is not the acquisition of driver gene mutations, but rather the expansion of the clone. Factors that control the conversion from clonal hematopoiesis to MPN disease include inherited predisposition, presence of additional mutations, and inflammation. The full extent of knowledge of the mutational landscape in individual MPN patients is now increasingly being used to predict outcome and chose the optimal therapy.
Topics: Humans; Primary Myelofibrosis; Calreticulin; Receptors, Thrombopoietin; Myeloproliferative Disorders; Polycythemia Vera; Thrombocythemia, Essential; Janus Kinase 2; Mutation
PubMed: 36347013
DOI: 10.1182/blood.2022017578 -
Cells May 2022Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein... (Review)
Review
Calreticulin is an endoplasmic Ca binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca pool in cardiomyocytes are critical for the maintenance of proper cardiac function.
Topics: Calcium; Calreticulin; Endoplasmic Reticulum; Myocytes, Cardiac; Sarcoplasmic Reticulum
PubMed: 35681417
DOI: 10.3390/cells11111722 -
Nature Apr 2023Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered. Most NK cells and some innate lymphoid cells...
Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered. Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor. Blockage of NKp46 inhibits NK killing of many cancer targets. Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death, flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of CALR, the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1)-deficient human (and Nrc1-deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells.
Topics: Animals; Humans; Mice; Alarmins; Calreticulin; Cell Membrane; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Immunity, Innate; Immunological Synapses; Killer Cells, Natural; Lung Neoplasms; Melanoma, Experimental; Natural Cytotoxicity Triggering Receptor 1; Zika Virus
PubMed: 37020026
DOI: 10.1038/s41586-023-05912-0 -
Journal of Cellular and Molecular... Aug 2019In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of... (Review)
Review
In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long-lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.
Topics: Animals; Antineoplastic Agents; Calreticulin; Combined Modality Therapy; Dendritic Cells; Endoplasmic Reticulum Stress; Humans; Immunogenic Cell Death; Immunotherapy; Mitochondrial Membranes; Nanoparticles; Neoplasms; Phototherapy; T-Lymphocytes; Tumor Microenvironment
PubMed: 31210425
DOI: 10.1111/jcmm.14356 -
Science (New York, N.Y.) Sep 2022Tissue-specific stem cells persist for a lifetime and can differentiate to maintain homeostasis or transform to initiate cancer. Despite their importance, there are no...
Tissue-specific stem cells persist for a lifetime and can differentiate to maintain homeostasis or transform to initiate cancer. Despite their importance, there are no described quality assurance mechanisms for newly formed stem cells. We observed intimate and specific interactions between macrophages and nascent blood stem cells in zebrafish embryos. Macrophage interactions frequently led to either removal of cytoplasmic material and stem cell division or complete engulfment and stem cell death. Stressed stem cells were marked by surface Calreticulin, which stimulated macrophage interactions. Using cellular barcoding, we found that Calreticulin knock-down or embryonic macrophage depletion reduced the number of stem cell clones that established adult hematopoiesis. Our work supports a model in which embryonic macrophages determine hematopoietic clonality by monitoring stem cell quality.
Topics: Animals; Apoptosis; Calbindin 2; Calreticulin; Cell Communication; Clonal Hematopoiesis; Embryo, Nonmammalian; Hematopoietic Stem Cells; Macrophages; Zebrafish; Zebrafish Proteins
PubMed: 36137040
DOI: 10.1126/science.abo4837 -
Pathology Oncology Research : POR Apr 2013Calreticulin (CRT) as a multi-functional endoplasmic reticulum protein is involved in a spectrum of cellular processes which ranges from calcium homeostasis and... (Review)
Review
Calreticulin (CRT) as a multi-functional endoplasmic reticulum protein is involved in a spectrum of cellular processes which ranges from calcium homeostasis and chaperoning to cell adhesion and finally malignant formation and progression. Previous studies have shown a contributing role for CRT in a range of different cancers. This present review will focus on the possible roles of CRT in the progression of malignant proliferation and the mechanisms involved in its contribution to cancer invasion.
Topics: Calreticulin; Carcinogenesis; Endoplasmic Reticulum; Humans; Neoplasms
PubMed: 23392843
DOI: 10.1007/s12253-012-9600-2 -
The New England Journal of Medicine Dec 2013Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with...
BACKGROUND
Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge.
METHODS
We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry.
RESULTS
Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients.
CONCLUSIONS
Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).
Topics: Amino Acid Sequence; Bone Marrow Diseases; Calreticulin; Exons; Humans; Janus Kinase 2; Leukemia, Myeloid; Molecular Sequence Data; Mutation; Myelodysplastic Syndromes; Neoplasms; Polymerase Chain Reaction; Primary Myelofibrosis; Sequence Analysis, DNA; Thrombocythemia, Essential
PubMed: 24325359
DOI: 10.1056/NEJMoa1312542 -
Blood Feb 2023
Topics: Humans; Calreticulin; Neoplasms; Computer Simulation; Biological Transport; Myeloproliferative Disorders
PubMed: 36821187
DOI: 10.1182/blood.2022018788 -
Hematology/oncology Clinics of North... Apr 2021Myeloproliferative neoplasms are hematopoietic stem cell disorders based on somatic mutations in JAK2, calreticulin, or MPL activating JAK-STAT signaling. Modern... (Review)
Review
Myeloproliferative neoplasms are hematopoietic stem cell disorders based on somatic mutations in JAK2, calreticulin, or MPL activating JAK-STAT signaling. Modern sequencing efforts have revealed the genomic landscape of myeloproliferative neoplasms with additional genetic alterations mainly in epigenetic modifiers and splicing factors. High molecular risk mutations with adverse outcomes have been identified and clonal evolution may promote progression to fibrosis and acute myeloid leukemia. JAK2V617F is recurrently detected in clonal hematopoiesis of indeterminate potential with increased risk for vascular events. Insights into the genetics of myeloproliferative neoplasms has facilitated diagnosis and prognostication and poses novel candidates for targeted therapeutic intervention.
Topics: Calreticulin; Hematopoietic Stem Cells; Humans; Janus Kinase 2; Mutation; Myeloproliferative Disorders; Neoplasms; STAT Transcription Factors; Signal Transduction
PubMed: 33641865
DOI: 10.1016/j.hoc.2020.12.002