Other mutations described in MPN, but also in other h Dermatological malignancy Th are MutatIons in the receiver singer thrombopo Retina at codon 515, isocitrate dehydrogenase gene family, gender K mme Like zus USEFUL Gen 1, casitas B-lineage lymphoma proto-oncogene, the element of TET oncogene 2, and Ikaros family zinc finger gene-1. F these mutations Rdern h Hematopoietic proliferation Ethics by other means, that the activation of cytokines and JAK signaling bcl-2 they h Were more often in non-MPN PV, ET MFP, myelodysplastic syndromes, secondary Re Leuk Mie acutemyeloid detected and blastic transformation phase of the NPP. There is a relationship between the genetic mechanism of MPN and in response to different treatments. For example, 40-50% of patients with primary Ren and MV AND JAK2V617F mutation Undo length The proportion of JAK2 mutant DNA was experienced.
About 20% of PMF and ET patients leading MPLmutations no decrease in the proportion of mutated DNA MPL when treated with KU-0063794 inhibitors of JAK2, but they did when treated with the biological response modifiers. New biological properties of JAK2 are currently being investigated. Recently it was shown that not only JAK2 localized in the cytoplasm of h Hematopoietic cells Ethical where JAK2 plays an r In cytokine signaling pathway, but also the core of the h Hematopoietic cells Ethical. In the nucleus, a hyperactive induced phosphorylation of histone H3 at the JAK2 tyrosine residue 41, releasing the transcriptional repressor 1alfa chromatin and heterochromatin which suppresses transcriptional activation of genes by HP1A as LMO2 oncogene. LMO2 k Nnte An r Pathogenicity t In ofMPN.
It is noteworthy that the phosphorylation of JAK2 H3Y41 hyperactive ben justified, Which means that the activation of different ways with different effectors and different target genes JAK2 is involved in the pathogenesis of MPN. in era of JAK2 inhibitors, this discovery opens new M opportunities for combined therapeutic targets that may benefit patients with MPN k. Second Gegenw Rtige therapies for BCR ABL1 NegativeMPN on JAK2 inhibitors and their combinations based hyper activation of JAK2 is a critical step in the pathogenesis of BCR ABL1 negative MPN classic. Autonomous activation of JAK2 kinase Dom ne the following persistent phosphorylation of STAT and MAPK proteins Occur in patients with or without mutations in JAK2V617F. JAK2 inhibitors have been developed for more suppress cytokine signaling by cytoplasmic JAK2 gene induced hyperactive.
JAK2 inhibitors competing for the ATP binding pocket of the tyrosine kinase JAK2 Dom ne. Since JAK2V617F mutation is au Outside of the ATP-binding site, must JAK2 inhibitors not differentiate between mutated JAK2 and JAK2 genes. Consequently k Can JAK2 inhibitors in patients withMPN be used independently Ngig from the state of JAK2. Today, several JAK2 inhibitors in clinical trials in Europe and the U.S. and others are in the pr Clinical development. INCB018424 Ruxolitinib known is a potent and selective inhibitor of JAK1 and JAK2. It has been used in patients with MFP where INCB018424 reduced proinflammatory cytokines by inhibition of the signal and removes the JAK1 phosphorylated STAT3 by inhibiting JAK2, independently Dependent.