Project Title: Inhibition of deubiquitinating enzymes as a novel targeted therapy for JAK2-dependent myeloid malignancies
Mutations in the JAK2 gene resulting in constitutive kinase activation are the most common genetic event in myeloproliferative neoplasms (MPN). JAK2 kinase inhibitors provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility. Here we propose a strategy to specifically target JAK2-V617F for degradation while sparing wt JAK2. We show that proteasome-mediated degradation of mutant JAK2 is regulated by specific members of the large (100+) family of deubiquitinating enzyme(s) (DUBs) responsible for cleavage of degradative ubiquitin tags. We screened a focused-library of most known small molecule DUBs inhibitors to identify compounds that induced degradation of JAK2-V617F but not wt JAK2. The compounds identified were then shown to selectively inhibit growth of JAK2-V617F-positive leukemia cells without impacting growth of wt JAK2expressing cells in the same model. Our preliminary data identify USP7 and USP10 as candidate DUBs responsible for the observed effects. In this application from our team of biologists and chemists, we propose to identify all DUB mediators of JAK2-V617F (Aim 1), and to chemically optimize and characterize lead compounds in preclinical models of MPN (Aim 2). These studies provide a novel strategy to obtain a real therapeutic window in targeting JAK2 signaling in MPN.