Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance

Abstract

Aberrant activation of the JAK/STAT pathway has been reported in a variety of disease states, including inflammatory conditions, hematologic malignancies, and solid tumors. For instance, a large proportion of patients with myeloproliferative neoplasms (MPN) carry the acquired gain-of-function JAK2 V617F somatic mutation. This knowledge has dramatically improved our understanding of the pathogenesis of MPNs and has facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway, now recognized as a common underlying biologic abnormality in MPNs. Ruxolitinib is an oral JAK1 and JAK2 inhibitor that has recently been approved for the treatment of myelofibrosis and has been tested against other hematologic malignancies. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials for patients with MPNs, lymphoma, and solid tumors such as breast or pancreatic cancer. Despite the significant clinical activity exhibited by these agents in myelofibrosis, some patients fail to respond or progress during JAK kinase inhibitor therapy. Recent reports have shed light into the mechanisms of resistance to JAK inhibitor therapy. Several approaches hold promise to overcome such resistance.

FIGURE 1. JAK/STAT pathway in myeloproliferative neoplasms

Upon cytokine binding, JAK2 molecules are recruited and activated by cytokine receptors, which results in phosphorylation of downstream signaling pathways such as PI3K, RAS, and STAT3/5. STAT heterodimers and homodimers translocate to the nucleus and bind cognate DNA sequences at the promoter regions of genes involved in proliferation and apoptosis. In the presence of JAK2^V617F mutations, the JAK/STAT pathway is constitutive activated. JAK2 inhibitors abrogate the JAK/STAT pathway through the inhibition of the kinase activity of JAK2^V617F kinase. The activity of the JAK2/STAT pathway is negatively regulated by SOCS1 and LNK. Recently, JAK2 and JAK2^V617F kinase have been shown to localize to the nucleus of hematopoietic precursors where it phosphorylates histone H3 (H3Y41), thus preventing its binding to the repressor heterochromatin protein 1 alpha (HP1α). The latter results in increased expression of the oncogene lmo2. These effects are reversible upon exposure to JAK2 inhibitors. JAK2^V617F also binds and phosphorylates the arginine methyltransferase PRMT5, which hampers its interaction with methylosome protein 50 (MEP50), thus decreasing global arginine methylation of histones H2A and H4. The figure is modified from Quintás-Cardama, et al (reference #59)