The Janus family
kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-
receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in
polycythemia vera (PV) and other myeloproliferative
neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with
essential thrombocythemia (ET) and
primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2,
cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2
ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects.
Ruxolitinib causes a significant reduction in the level of pro-inflammatory
cytokines. Another inhibitor,
CYT387, improves
anemia. Many other JAK2 inhibitors such as
TG101348 or
SAR302503,
SB1518,
CEP701 and
LY2784544 are now under investigation for MPN development. In contrast
tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and
immunological diseases, including
rheumatoid arthritis,
psoriasis,
ulcerative colitis,
dry eye disease and in kidney transplant patients. In conclusion the use of
JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for
therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases.