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calreticulin myeloproliferative

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https://www.readbyqxmd.com/read/29288169/defining-the-requirements-for-the-pathogenic-interaction-between-mutant-calreticulin-and-mpl-in-mpn
#1
Shannon Elf, Nouran S Abdelfattah, April J Baral, Danielle Beeson, Jeanne F Rivera, Amy Ko, Natalie Florescu, Gabriel Birrane, Edwin Chen, Ann Mullally
Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms (MPN). Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C-terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells, binding alone is insufficient for cytokine independent growth...
December 29, 2017: Blood
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#2
REVIEW
Prithviraj Bose, Jason Gotlib, Claire N Harrison, Srdan Verstovsek
The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29258411/calreticulin-affects-hematopoietic-stem-progenitor-cell-fate-by-impacting-erythroid-and-megakaryocytic-differentiation
#3
Simona Salati, Zelia Prudente, Elena Genovese, Valentina Pennucci, Sebastiano Rontauroli, Niccolo' Bartalucci, Carmela Mannarelli, Samantha Ruberti, Roberta Zini, Chiara Rossi, Elisa Bianchi, Paola Guglielmelli, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini
Calreticulin (CALR) is a chaperone protein that localizes primarily to the endoplasmic reticulum (ER) lumen where it is responsible for the control of proper folding of neo-synthesized glycoproteins and for the retention of calcium. Recently, mutations affecting exon 9 of the CALR gene have been described in approximately 40% of patients with myeloproliferative neoplasms (MPNs). Although the role of mutated CALR in the development of MPNs has begun to be clarified, there are still no data available on the function of wild-type (WT) CALR during physiological hematopoiesis...
December 19, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29222295/myeloproliferative-neoplasms-from-origins-to-outcomes
#4
REVIEW
Jyoti Nangalia, Anthony R Green
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29218307/calreticulin-challenges-posed-by-the-intrinsically-disordered-nature-of-calreticulin-to-the-study-of-its-function
#5
Lilian Varricchio, Mario Falchi, Massimiliano Dall'Ora, Caterina De Benedittis, Alessandra Ruggeri, Vladimir N Uversky, Anna Rita Migliaccio
Calreticulin is a Ca2+-binding chaperone protein, which resides mainly in the endoplasmic reticulum but also found in other cellular compartments including the plasma membrane. In addition to Ca2+, calreticulin binds and regulates almost all proteins and most of the mRNAs deciding their intracellular fate. The potential functions of calreticulin are so numerous that identification of all of them is becoming a nightmare. Still the recent discovery that patients affected by the Philadelphia-negative myeloproliferative disorders essential thrombocytemia or primary myelofibrosis not harboring JAK2 mutations carry instead calreticulin mutations disrupting its C-terminal domain has highlighted the clinical need to gain a deeper understanding of the biological activity of this protein...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29212804/myeloproliferative-neoplasms-from-origins-to-outcomes
#6
REVIEW
Jyoti Nangalia, Anthony R Green
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation...
December 7, 2017: Blood
https://www.readbyqxmd.com/read/29194068/polycythemia-vera-and-essential-thrombocythemia-algorithmic-approach
#7
Alessandro M Vannucchi, Paola Guglielmelli, Ayalew Tefferi
PURPOSE OF REVIEW: To describe an algorithm-based approach, whenever available, to the diagnosis, the risk stratification criteria informing therapy and the current management of polycythemia vera and essential thrombocythemia. RECENT FINDINGS: Description of recurrent genetic abnormalities in driver genes, including Janus Kinase 2 (JAK2), myeloproliferative leukemia and calreticulin, a better appreciation of the key diagnostic role of bone marrow features, results of large epidemiologic studies and a few but landmark controlled clinical trials produced in the last decade, all resulted in a reappraisal of the approach to polycythemia vera and essential thrombocythemia...
November 30, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29164670/driver-mutations-and-prognosis-in-primary-myelofibrosis-mayo-careggi-mpn-alliance-study-of-1-095-patients
#8
Ayalew Tefferi, Maura Nicolosi, Mythri Mudireddy, Natasha Szuber, Christy M Finke, Terra L Lasho, Curtis A Hanson, Rhett P Ketterling, Animesh Pardanani, Naseema Gangat, Carmela Mannarelli, Tiziana Fanelli, Paola Guglielmelli, Alessandro M Vannucchi
The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative...
November 22, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#9
Martin Griesshammer, Parvis Sadjadian
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythaemia vera (PV) and essential thrombocythaemia (ET). They are characterized by stem cell-derived clonal proliferation, harbour Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukaemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials...
November 14, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29123956/mutations-in-jak2-and-calreticulin-genes-are-associated-with-specific-alterations-of-the-immune-system-in-myelofibrosis
#10
Marco Romano, Daria Sollazzo, Sara Trabanelli, Martina Barone, Nicola Polverelli, Margherita Perricone, Dorian Forte, Simona Luatti, Michele Cavo, Nicola Vianelli, Camilla Jandus, Francesca Palandri, Lucia Catani
Myelofibrosis (MF) is a clonal neoplasia associated with chronic inflammation due to aberrant cytokine production. Mutations in Janus Kinase-2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia protein (MPL) genes have been recently associated to MF and they all activate the JAK/STAT signaling pathway. Since this pathway is essential in shaping the immune response, we investigated the role of circulating immune subsets and cytokines in 38 patients (20 carrying JAK2(V617F),13 exon-9 CALR mutation and 5 triple negative)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28978835/effect-of-mutation-on-diagnosis-risk-stratification-and-treatment-decisions-in-philadelphia-negative-myeloproliferative-neoplasms
#11
Keita Kirito
Since the discovery of the activating mutation of JAK2, known as JAK2V617F, our understanding of mutation profiles, and the biological significance of this mutation in Philadelphia-negative (Ph-) MPNs has drastically changed over the last decade. Mutations of the thrombopoietin receptor MPL and chaperone protein calreticulin gene also induce aberrant activation of JAK and downstream molecules, including STAT proteins, and contribute to the development of MPNs. Mutations of the genes JAK2, MPL, and calreticulin are referred to as "driver mutations" for MPNs...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28741795/novel-molecular-mechanism-of-cellular-transformation-by-a-mutant-molecular-chaperone-in-myeloproliferative-neoplasms
#12
REVIEW
Marito Araki, Norio Komatsu
Deregulation of the cytokine-receptor signaling pathway plays a significant role in tumorigenesis. Such deregulation is frequently caused by alterations in the genes involved in the signaling pathway. At the end of 2013, recurrent somatic mutations in the calreticulin (CALR) gene that encodes a molecular chaperone were identified in a subset of patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). The present review focuses on the role of CALR mutations in the oncogenic transformations observed in MPN...
October 2017: Cancer Science
https://www.readbyqxmd.com/read/28725653/calr-positive-myeloproliferative-disorder-in-a-patient-with-ph-positive-chronic-myeloid-leukemia-in-durable-treatment-free-remission-a-case-report
#13
Irene Dogliotti, Carmen Fava, Anna Serra, Enrico Gottardi, Filomena Daraio, Francesca Carnuccio, Emilia Giugliano, Monica Bocchia, Giuseppe Saglio, Giovanna Rege-Cambrin
Current diagnostic criteria for Philadelphia-negative myeloproliferative neoplasia (MPN) have been redefined by the discovery of Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL) and calreticulin (CALR) genetic alterations. Only few cases of coexistence of CALR-mutated MPN and Philadelphia-positive chronic myeloid leukemia (CML) have been described so far. Here we report the case of a patient with CML diagnosed in 2001, treated with imatinib and pegylated interferon (IFN) frontline. She reached complete molecular remission (CMR) and discontinued imatinib, maintaining treatment free remission...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28673392/mechanisms-of-resistance-to-jak2-inhibitors-in-myeloproliferative-neoplasms
#14
REVIEW
Sara C Meyer
Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28640953/overview-of-transgenic-mouse-models-of-myeloproliferative-neoplasms-mpns
#15
REVIEW
Andrew Dunbar, Abbas Nazir, Ross Levine
Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies...
June 22, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28625126/enhanced-risk-for-specific-somatic-myeloproliferative-neoplastic-mutations-in-patients-with-stroke
#16
Chih-Cheng Chen, Chia-Chen Hsu, Cih-En Huang, Yi-Yang Chen, Jrhau Lung, Hsing-Ying Ho, Chian-Pei Li, Jiann-Der Lee
BACKGROUND: Somatic mutations of Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are the major clonal molecules that drive the pathogenesis of myeloproliferative neoplasms (MPN). It is well recognized that MPN patients carry an excessive risk of thrombohemorrhagic complications. However, little is known about the prevalence of these clonal markers in patients with cerebral vascular disease. METHODS: To address this issue, 153 consecutive stroke patients in Taiwan were enrolled in the study...
2017: Current Neurovascular Research
https://www.readbyqxmd.com/read/28589084/calreticulin-in-essential-thrombocythemia-stressing-out-the-megakaryocyte-nucleus
#17
Francisco Jose Iborra, Petros Papadopoulos
Calreticulin (CALR) is a multifaceted protein primarily involved in intracellular protein control processes. The identification of CALR mutations in essential thrombocythemia (ET) and primary myelofibrosis that are mutually exclusive with the JAK2 V617F mutation has stirred an intensive research interest about the molecular functions of CALR and its mutants in myeloproliferative neoplasms (MPNs) and its diagnostic/prognostic value. The recently characterized protein-protein interaction of CALR mutants and MPL receptor has advanced our knowledge on the functional role of CALR mutants in thrombocythemia but it has also uncovered limitations of the current established research models...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28529308/assessing-the-thrombotic-risk-of-patients-with-essential-thrombocythemia-in-the-genomic-era
#18
REVIEW
L Falchi, H M Kantarjian, S Verstovsek
The molecular characterization of myeloproliferative neoplasms, including essential thrombocythemia (ET), has enabled deeper understanding of their pathogenesis. A driver lesion, namely, Janus kinase (JAK)2V617F, calreticulin (CALR) or myeloproliferative leukemia (MPL) gene mutation can be identified in the vast majority of patients. Each of these mutations is associated with distinct clinical features and may modulate the patients' clinical course, risk of complications, including vascular events, and survival...
September 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28503969/essential-thrombocythemia-a-review-of-the-clinical-features-diagnostic-challenges-and-treatment-modalities-in-the-era-of-molecular-discovery
#19
Sarah Chuzi, Brady L Stein
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that is associated with diminished quality of life, thrombohemorrhagic complications, and transformation to myelofibrosis (MF) and acute leukemia (AML). The important recent discoveries of driver mutations, including the calreticulin gene in addition to JAK2 and MPL, have led to a greater understanding of disease pathogenesis and set the stage for the advent of more sophisticated prognostic, diagnostic, and therapeutic strategies. In this paper we summarize recent studies describing the molecular basis of ET...
December 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28483676/selective-testing-for-calreticulin-gene-mutations-in-patients-with-splanchnic-vein-thrombosis-a-prospective-cohort-study
#20
Johanne Poisson, Aurélie Plessier, Jean-Jacques Kiladjian, Fanny Turon, Bruno Cassinat, Annalisa Andreoli, Emmanuelle De Raucourt, Odile Goria, Kamal Zekrini, Christophe Bureau, Florence Lorre, Francisco Cervantes, Dolors Colomer, François Durand, Juan-Carlos Garcia-Pagan, Nicole Casadevall, Dominique-Charles Valla, Pierre-Emmanuel Rautou, Christophe Marzac
BACKGROUND AND AIMS: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (JAK2)(V617F) mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing...
May 5, 2017: Journal of Hepatology
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