The advances in molecular insights, especially the discovery of the Janus kinase 2 (JAK2) V617F mutation and its role in JAK-STAT pathway dysregulation, led to the development of the JAK inhibitor ruxolitinib, which currently represents the cornerstone of medical therapy in MF and hydroxyurea-resistant/intolerant PV.
Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis.
Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs.
Bioinformatics analysis of the drug-responsive genes showed that the JAK-STAT pathway was activated in the cured younger brother, which is opposite to the pathway inhibition observed in adult PMF cases following treatment.
The myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) display distinct clinical and pathologic features but are characterized by mutations in JAK2, MPL, and CALR leading to activation of the JAK-STAT pathway.
Ongoing and planned clinical trials of these agents, either alone or in various combinations with other targeted therapies, such as JAK-STAT or histone deacetylase inhibitors, and anti-fibrotic agents, will reveal the full potential of immune therapies in MF.
These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis.
Agents targeting the JAK-STAT pathway have dominated the investigational therapeutic portfolio over the last five years resulting in the first and only approved agent for the treatment of patients with myelofibrosis (MF).
These results suggested that JAK-STAT pathway activation might contribute to the pathogenesis of JAK2-negative myeloproliferative disorders, and led to the discovery of an activating mutation in the thrombopoietin receptor in JAK2-negative myelofibrosis and essential thrombocytosis.