Icse

Dysregulated JAK signaling in Myelofibrosis and other Myeloproliferative Neoplasms

Myelofibrosis or MF is a typeof Myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, anemia and constitutional symptoms such as weight loss, night sweats and fever.
Recently, dysregulation of the JAKsignaling pathway was recognized as the key feature of MF and other myeloproliferative neoplasms including Polycythaemia Vera and the essential thrombocythaemia.
The JAK pathway transmits cytokinesignals from cytokine and under normal conditions is under strict control to ensure proper blood cell development and function.
The genes kinese of JAKS a cytoplasmic non receptive tyrosine kinesisthat transmits signals from activity inside de chondricus receptors to the nucleus.
They do this by phosphorylating stat molecules which allows them to enter the nucleus, binds to genes and initiatetranscription. Hematopeietic growth factors such as erythropoietin and thrombopoietin use mainly JAK 2.
In contrast pro inflammatory cytokines such as interleukins use primarily JAK 1 often inassociation with other JAKS.
In patients with Myeloproliferative neoplasms more than 10 mutations affecting JAK proteins and other members of the JAK pathway have been identified.
These mutations lead toconstative activation of JAK signaling which contributes to the development of myeloproliferative neoplasms.
Dysregulating JAK signaling can occur even in the absence of mutations with extremely highlevels of circulating inflammatory cytokines often seen in these patients result in excessive activation of both, JAK 1 and JAK 2
Crearly, there’s a need to investigate JAK 1 and JAK 2 inhibitors inthese diseases.
The overlapping nature of JAK signaling pathways suggest that there’s maybe a rush now to test inhibition on both JAK 1 and JAK 2.

Señalamiento de la regulación de JAK en...