Mutations, inflammation and phenotype of myeloproliferative neoplasms

Knowledge on the myeloproliferative neoplasms (MPNs) – polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) – has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (ASXL1, DNMT3A, TET2, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies

Gα16 protein expression is up- and down-regulated following T-cell activation: disruption of this regulation impairs activation-induced cell responses

AbstractThe role of heterotrimeric G proteins in T-cell activation is poorly understood. Here we show that in normal, mature human T-cells, expression of Gα16, the 43 kDa α subunit of G16, varies widely, depending on T-cell activation status. Quiescent blood lymphocytes strongly up-regulate Gα16 after Leuco A stimulation: protein expression of Gα16 is maximal at day 4, then decreases. Consistently, in human T-cell clones, expression of Gα16 is high in the first week following activation and decreases rapidly within the second week. In addition, permanent disruption of regulated Gα16 expression in Jurkat T-cells by stable overexpression of 43 kDa Gα16 inhibited Leuco A-induced interleukin-2 production, CD69 up-regulation and cell apoptosis (by 58%, 46% and 74%, respectively), suggesting that coordinate regulation of Gα16 expression is necessary for optimal activation-induced T-cell responses, and that Gα16 proteins may be involved in the negative regulation of TCR signalling

Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation

Pathogenesis of myeloproliferative neoplasms : More than mutations

International audience.

Mutations, inflammation and phenotype of myeloproliferative neoplasms

International audienceKnowledge on the myeloproliferative neoplasms (MPNs) – polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) – has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2 V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations ( ASXL1, DNMT3A, TET2 , others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies

Jak2, cytokines et récepteurs dans la polyglobulie de Vaquez

La polyglobulie de Vaquez (PV) appartient à la famille des syndromes myéloprolifératifs (SMP). C'est une maladie clonale dont l'origine se situe au niveau d'un progéniteur multipotent. En 2005, la description de la mutation JAK2V617F et sa présence dans 95% des cas de PV, à la fois à l état homozygote et hétérozygote, a été le point de départ de nouvelles interrogations concernant les mécanismes moléculaires impliqués dans la pathogénèse de cette maladie. L objectif de ce travail a été, dans un premier temps, de mettre au point une technique sensible de PCR quantitative spécifique d allèle. Cette technique a permis d étudier le niveau d expression de JAK2V617F chez les patients au diagnostic de SMP. Nous avons, ensuite, utilisé cette même approche pour étudier l importance de la détection de JAK2V617F pour la détection de SMP latent dans les présentations atypiques comme les thromboses digestives profondes et les anémies réfractaires sidéroblastiques. Nous avons également, en collaboration, déterminé que quand un SMP positif pour JAK2V617F se transforme en leucémie aigue myéloïde, celle-ci est fréquemment négative pour la mutation. Il a également été mis en évidence que les clones JAK2V617F positifs et négatifs peuvent se développer à partir d un ancêtre commun. Enfin, nous avons décrit dans la PV, la dérégulation de la production, au niveau protéique et ARN messager, de plusieurs cytokines hématopoïétiques et de leur voie de signalisation (IL-11, IL-6, gp130, JAK2, STAT3). Cette dérégulation participe à l'hématopoïèse anormale dans la PV. Ces mécanismes, indépendants de JAK2V617F, semblent maintenir l'équilibre entre les voies JAK2V617F/STAT5 et JAK2/STAT3.Polycythemia Vera (PV) belongs to the family of myeloproliferative disorders (MPD). It is a clonal disease arising from a multipotent progenitor. In 2005, the JAK2V617F mutation was discovered as a MPD specific mutation present in more than 95% of PV patients both at homozygous and heterozygous state. This discovery was the starting point of a new area in the understanding of molecular mechanisms invloved in MPD pathogenesis. The aim of our work was, first to set up an assay of allele specific quantitative PCR. Thanks to this assay, we were able to study the importance of JAK2V617F mutation at diagnosis of MPD. We also used this assay to investigate the relevance of JAK2V617F detection for the diagnosis of latent MPD in atypical presentations like splanchnic vein thrombosis and refractory anemia with ringed sideroblasts. In addition, in collaboration, we have determined that positive JAK2V617F MPD often transform into JAK2V617F negative acute myeloid leukemia, and that both clones may derive from the same JAK2V617F negative ancestral clone. Finally, we have described , in PV patients, elevated production of hematopoietic cytokines (IL-11, IL-6), both at the protein and messenger RNA level. Their signaling pathway (gp130, JAK2, STAT3) was also dysregulated and this pathway is involved in PV abnormal hematopoiesis. This mecHanism is independent from JAK2V617F and seems to maintain the balance between the JAK2V617F/STAT5 and JAK2/STAT3 pathways.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

L'anémie en cancérologie (de la physiopathologie à la prise en charge)

L'anémie est une complication commune chez les patients atteints de cancer et d'autant plus qu'ils reçoivent un traitement par chimiothérapie. Elle a une incidence aussi bien sur la qualité de vie des patients que sur l'évolution de la maladie. Si le traitement de l'anémie passe tout d'abord par le traitement de la maladie causale, la synthèse de l'EPO recombinante humaine a considérablement amélioré la prise en charge des patients anémiques, augmentant les taux d'hémoglobine et réduisant les besoins transfusionnels. Alors, dans un contexte global de précautions sanitaires et de maîtrise des dépenses de santé, la mise à disposition de l'érythropoïétine et sa large utilisation aujourd'hui sont des vecteurs puissants d'interrogations sur les pratiques, transfusionnelles et d'utilisation de la r-HuEPO. Par conséquent, cela nous entraîne à faire une révision complète et approfondie sur l'anémie : physiopathologie, fréquence, symptomatologie et retentissement clinique.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Editorial: The Role of Microorganisms in Multiple Myeloma

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