Constitutional genetic association with CALR mutations?

Eder-Azanza, Laura; Evans, Paul; Wickham, C L; Akiki, Susanna; Vizmanos, José Luis; Chase, Andrew; Cross, Nicholas C.P.

doi:10.1038/leu.2015.186

Cited by 1 publication

(1 citation statement)

References 14 publications

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“…The SNPs in TERT , MECOM , and JAK2 (other than 46/1) appear to predispose to JAK2V617F -negative MPNs, whereas the HBS1L/MYB SNPs predispose only to JAK2V617F ET 74 . An SNP located in the CALR gene could favor CALR mutations 75 , but this result remains controversial 76 . It is unknown whether other genetic determinants that regulate blood cell levels regulate the phenotype of MPNs.…”

Section: Factors Other Than Acquired Somatic Mutations Are Involved Imentioning

confidence: 99%

Recent advances in understanding myelofibrosis and essential thrombocythemia

2016

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The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery of CALR mutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient’s constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the development of JAK2 inhibitors.

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Section: Factors Other Than Acquired Somatic Mutations Are Involved Imentioning

confidence: 99%