1. Mutant Calreticulin in the Myeloproliferative Neoplasms
- Author
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Daniel Prins, Jacob Grinfeld, Anthony R. Green, Thorsten Klampfl, Carlos Gonzalez Arias, Green, Tony [0000-0002-9795-0218], and Apollo - University of Cambridge Repository
- Subjects
Lineage (genetic) ,Mutant ,32 Biomedical and Clinical Sciences ,Review Article ,Rare Diseases ,medicine ,Genetics ,2.1 Biological and endogenous factors ,Myelofibrosis ,Cancer ,Thrombopoietin receptor ,2 Aetiology ,Janus kinase 2 ,biology ,lcsh:RC633-647.5 ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,medicine.disease ,Haematopoiesis ,3201 Cardiovascular Medicine and Haematology ,FOS: Biological sciences ,biology.protein ,Cancer research ,Stem cell ,Calreticulin - Abstract
Mutations in the gene for calreticulin (CALR) were identified in the myeloproliferative neoplasms (MPNs) essential thrombocythaemia (ET) and primary myelofibrosis (MF) in 2013; in combination with previously described mutations in JAK2 and MPL, driver mutations have now been described for the majority of MPN patients. In subsequent years, researchers have begun to unravel the mechanisms by which mutant CALR drives transformation and to understand their clinical implications. Mutant CALR activates the thrombopoietin receptor (MPL), causing constitutive activation of Janus kinase 2 (JAK2) signaling and cytokine independent growth in vitro. Mouse models show increased numbers of hematopoietic stem cells (HSCs) and overproduction of megakaryocytic lineage cells with associated thrombocytosis. In the clinic, detection of CALR mutations has been embedded in World Health Organization and other international diagnostic guidelines. Distinct clinical and laboratory associations of CALR mutations have been identified together with their prognostic significance, with CALR mutant patients showing increased overall survival. The discovery and subsequent study of CALR mutations have illuminated novel aspects of megakaryopoiesis and raised the possibility of new therapeutic approaches.
- Published
- 2020