JAK2 the future: therapeutic strategies for JAK-dependent malignancies

The Janus kinase (JAK) proteins are a family of intracellular nonreceptor tyrosine kinases involved in cytokine signaling via the JAK–STAT (signal transducers and activators of transcription) pathway. Genetic studies have identified somatic JAK2V617F mutations and other mutant alleles that activate JAK–STAT signaling in most patients with myeloproliferative neoplasms (MPNs). As a result, JAK inhibitors have been developed to treat various malignancies and have been shown to be efficacious in both preclinical and clinical settings. However, available ATP-competitive JAK (type I) inhibitors are associated with dose-dependent toxicities, and do not yet reduce disease burden in MPN patients. Recent studies suggest that genetic and epigenetic mechanisms can cause insensitivity to type I JAK inhibitors. Novel therapies include the development of type II JAK inhibitors and the use of alternative strategies to abrogate JAK–STAT signaling, perhaps with histone deacetylase (HDAC) and heat shock protein 90 (HSP90) inhibitors. These innovative therapies may translate to treatment of other diseases that are dependent on JAK signaling, including B-precursor acute lymphoblastic leukemia (B-ALL).