CALR mutations screening in wild type JAK2V617F and MPLW515K/L Brazilian myeloproliferative neoplasm patients

Nunes, Daniela Prudente Teixeira; Lima, Luciene Terezina de; Chauffaille, Maria de Lourdes Lopes Ferrari; Mitne‐Neto, Miguel; Santos, Marcos Tadeu dos; Cliquet, Marcelo Gil; Guerra-Shinohara, Elvira María

doi:10.1016/j.bcmd.2015.07.005

Cited by 16 publications

(22 citation statements)

References 46 publications

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“…CALR was also identified in a subset of patients with refractory anemia with ringed sideroblasts associated with marked thrombocytosis, but not in other hematological malignancies (Klampfl, et al 2013). These finding were confirmed by several research groups (Grinsztejn, et al 2016;Haslam, et al 2016;Labastida-Mercado, et al 2015;Machado-Neto, et al 2015;Monte-Mor, et al 2016;Nunes, et al 2015;Shirane, et al 2015;Wojtaszewska, et al 2015;. Over fifty different CALR mutations in exon 9 have been described, however the most frequent mutations (approximately 80%) are classified as type-1 (L367fs*46, deletion of 52bp) and type-2 (K385fs*47, insertion of 5bp).…”

Section: Myeloproliferative Neoplasmssupporting

confidence: 68%

CALR (calreticulin)

Machado-Neto¹,

Campos²,

Trainaen³

2018

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Calreticulin (CALR) is a multifunctional protein involved in molecular chaperoning and calcium homeostasis. CALR has also been associated with proliferation, cell cycle progression, migration, invasion and anoikis resistance in cancer cells. The prognostic impact of CALR expression is yet to be elucidated, however in some types of cancer, high CALR expression has been related to worse clinical outcomes. Notably, the discovery of recurrent mutations in the exon 9 of the CALR gene in myeloproliferative neoplasms has opened a new round of investigations. The present review contains data on CALR DNA/RNA, protein encoded and function.

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Section: Myeloproliferative Neoplasmssupporting

confidence: 68%

CALR (calreticulin)

Machado-Neto¹,

Campos²,

Trainaen³

2018

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Further analysis by PCR found that 25–35% of patients who did not possess JAK 2 or MPL mutations had mutations in the CALR gene 22 24. Subsequent studies have also found that CALR mutations were detected in 60–80% of patients with ET and PMF who lacked JAK 2 and MPL mutations 23 . CALR mutations were not detected in patients with polycythaemia vera (PV) 22 25…”

Section: Mutation Of the Calr Genementioning

confidence: 95%

TheCalreticulingene and myeloproliferative neoplasms

Clinton

McMullin

2016

J Clin Pathol

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The Philadelphia negative myeloproliferative neoplasms include polycythaemia vera (PV), essential thrombocytopenia (ET) and primary myelofibrosis (PMF). Patients with these conditions were mainly thought to harbourJAK2V617Fmutations or anMyeloproliferative leukaemia(MPL) substitution. In 2013, two revolutionary studies identified recurrent mutations in a gene that encodes the protein calreticulin (CALR). This mutation was detected in patients with PMF and ET with non-mutatedJAK2orMPLbut was absent in patients with PV. TheCALRgene encodes the calreticulin protein, which is a multifactorial protein, mainly located in the endoplasmic reticulum in chromosome 19 and regulates calcium homeostasis, chaperones and has also been implicated in multiple cellular processes including cell signalling, regulation of gene expression, cell adhesion, autoimmunity and apoptosis. Somatic 52 bp deletions and recurrent 52 bp insertion mutations inCALRwere detected and all resulted in frameshift and clusters in exon 9 of the gene. This review will summarise the current knowledge on theCALRgene and mutation of the gene in pathological conditions and patient phenotypes.

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“…The need for studies on the function of CALR in human erythropoiesis was highlighted by the discovery of somatic mutations in exon 9 of CALR disrupting the C-terminal domain of CALR in patients with the Philadelphia-negative myeloproliferative neoplasms (MPNs) essential thrombocytopenia and primary myelofibrosis not harboring JAK2 mutations [17–19]. CALR mutations are instead not detectable in patients with the MPN polycythemia vera (PV), who harbor mostly (>90%) the gain-of-function JAK2 V617F mutation [17–19].…”

mentioning

confidence: 99%

“…CALR mutations are instead not detectable in patients with the MPN polycythemia vera (PV), who harbor mostly (>90%) the gain-of-function JAK2 V617F mutation [17–19]. Surprisingly, the phenotype of CALR + MPNs includes constitutive activation of JAK2 [17,18] and these patients respond to treatment with JAK inhibitors such as ruxolitinib [20,21].…”

mentioning

confidence: 99%

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

Falchi

Varricchio

Martelli

et al. 2017

Experimental Hematology

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Calreticulin (CALR) is a Ca2+-binding protein that shuttles among cellular compartments with proteins bound to its N/P domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+ fluxes prompted us to investigate the role of CALR in human erythropoiesis. As shown by Western blot analysis, erythroblasts generated in vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of CALR. However, Ca2+ regulated CALR conformation only in normal cells. Normal erythroblasts expressed mostly the N-terminal domain of CALR (N-CALR) on their cell surface (as shown by flow cytometry) and C-terminal domain (C-CALR) in their cytoplasm (as shown by confocal microscopy) and expression of both epitopes decreased with maturation. In the proerythroblast (proEry) cytoplasm, C-CALR was associated with the glucocorticoid receptor (GR), which initiated the stress response. In these cells, Ca2+ deprivation and inhibition of nuclear export increased GR nuclear localization while decreasing cytoplasmic detection of C-CALR and C-CALR/GR association and proliferation in response to the GR agonist dexamethasone (Dex). C-CALR/GR association and Dex responsiveness were instead increased by Ca2+ and erythropoietin. In contrast, JAK2V617F proErys expressed normal cell-surface levels of N-CALR but barely detectable cytoplasmic levels of C-CALR. These cells contained GR mainly in the nucleus and were Dex unresponsive. Ruxolitinib rescued cytoplasmic detection of C-CALR, C-CALR/GR association, and Dex responsiveness in JAK2V617F proErys and its effects were antagonized by nuclear export and Ca2+ flux inhibitors. These results indicates that Ca2+-induced conformational changes of CALR regulate nuclear export of GR in normal erythroblasts and that JAK2V617F deregulates this function in PV.

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CALR mutations screening in wild type JAK2V617F and MPLW515K/L Brazilian myeloproliferative neoplasm patients

Cited by 16 publications

References 46 publications

CALR (calreticulin)

CALR (calreticulin)

TheCalreticulingene and myeloproliferative neoplasms

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

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