JAK (Janus kinase) enzymes play key roles in normal blood development and immune functions.
JAKs are non-receptor protein tyrosine kinases that mediate signal transduction in pathways that regulate cell growth and cell survival.
The JAK family is comprised of JAK1, 2 and 3 and tyrosine kinase 2 (TYK2).
The JAK family is associated with receptors that lack of intrinsic kinase activity.
JAK kinases mediate biological effects of cytokines and growth factors by carrying cytokine receptor signals to signal transducer and activator of transcription proteins.
For a JAK dependent signaling to happen, ligand binding to a cognate transmembrane receptor attracts cytoplasmic JAKs to an intracellular protein interacting domain of the receptor.
Following the above molecular aggregation JAKs are activated by autophosphorylation of tyrosine residues, triggering cascade of signaling events with phosphorylation of signal transducers abd activators of transcription (STATs).
A single point mutation present in 80-95% of patients with polycythemia rubra vera, 50% of patients with myelofibrosis and 50% of patients with essential thrombocytosis, and may be present in chronic myelomonocytic leukemia.
Activating JAK2 mutations reported an approximately 99% of patients with P. vera (Pardanani A et al).
A somatic activating mutation encoding a valine to phenylalanine substitution at position 617 (V617F) in Janus kinase 2 (JAK2).
JAK has 2 kinase remains: The first is a kinase, and the second is a a pseudo-kinase.
The V617F JAk2 mutation is in the pseudo-kinase domain.
Jak2 V617F mutation present in >95% of patients with polycythemia vera, and in 50-60% of patients with essential thrombocytosis and primary myelofibrosis
A nonreceptor tyrosine kinase that signals between cytokine receptors and downstream targets, including STAT3 and STAT5 transcription factors.
Expression confers cytokine indpendent growth and increaed sensitivity to cytokines and activation of STAT5.
An acquired somatic process in sporadic myeloproliferative disorder.
A gain of function mutation.
Common GI malignancies and the pathway is hyperactived in many of solid tumors, but particularly the majority of GI cancers.
It is not treated by mutation in pathways per se, and it is up regulated via mechanisms related to inflammation.
Leads to tyrosine phosphorylation of JAK2 and phosphorylation of downstream effectors of STAT5 and ERK.
Erythroid precursors with this change are hypersensitive to erythropoietin.
Red blood cells from patients with V617F mutation exhibit erythropoietin independence in vitro studies.
The bone marrow in patients with JAK2 V617F mutations have atypical megakaryocytic hyperplasia, with or without reticulin fibrosis.
JAK2 V617F mutation also has been reported in chronic myelomonocytic leukemia and myelodysplastic/myeloproloferative malignancies with ring sideroblasts and thrombocytosis, with a frequency of 8-10% and 60%, respectively.
Rarely JAK2 involves exon 12 in PV.
JAK2 inhibitors have improved overall survival and disease related symptoms , and stabilized or improved bone marrow fibrosis in patients with polycythemia vera and primary myelofibrosis.
JAK2 inhibitors associated with increased risk of aggressive B-cell lymphomas.