The roles of JAK2 in DNA damage and repair in the myeloproliferative neoplasms: Opportunities for targeted therapy

The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a “mutagenic” phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN. On the other hand, JAK2 signaling normally induces DDR through activation of repair mediators such as Chk1, RAD51 and RECQL5. These opposing effects on DNA integrity in the setting of JAK2V617F have significant clinical implications and have led to the introduction of novel combinational therapies for these diseases. The inhibition of MDM2 with Nutlin-3 improves the efficacy of IFN-α via decreased p53 degradation, the combination of hydroxyurea with Ruxolitinib, and their combination with PARP inhibitors have significant anti-tumor effects. A better understanding of the implication of JAK2 in the development and repair of DNA damage can improve our understanding of the biology of these neoplasms, meliorate the risk stratification of our patients and enrich our therapeutic armamentarium.