Targeting DESI2 as a Novel Therapeutic Strategy for JAK2‐Mutant Leukemias

Abstract The JAK2‐V617F mutation is the most common genetic alteration in myeloproliferative neoplasms (MPN), which can progress to secondary acute myeloid leukemia (sAML), a chemotherapy‐resistant disease with limited treatment options and a poor prognosis. Although the JAK1/2 inhibitor Ruxolitinib is clinically approved, its efficacy is limited by toxicity to normal cells and the development of drug resistance. Here, the deSUMOylase DESI2 is identified as a novel component of the JAK2‐V617F complex by mass spectrometry‐based proteomics. Mechanistically, DESI2 selectively binds to and stabilizes JAK2‐V617F by mediating its deSUMOylation and deubiquitination at lysine 962 (K962). Importantly, DESI2 protein is specifically and highly expressed in JAK2‐mutant‐driven cell lines and MPN primary clinical samples, suggesting its potential role in JAK2‐V617F regulation and disease progression. Genetic depletion of DESI2 suppresses both JAK2 mutant cell growth and MPN disease onset in vitro and in vivo. Moreover, through a compound screen, followed by chemical proteomics and compound optimization, WWQ‐03‐012 is discovered, which selectively degrades mutant JAK2, induces primary leukemia cells death, and inhibits MPN progression through targeting DESI2 enzymatic activity in vitro and in vivo. These studies provide a novel therapeutic strategy against mutated JAK2 signaling in MPN and sAML.