Background/Aim: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. Materials and Methods: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice. The disease severity and treatment effect with a JAK2 inhibitor was compared between Jak2VF and Jak2VF/Tyk2KO mice. Results: Both types of mice developed MPN, and there were no differences in peripheral blood counts, spleen weight, or survival period. Upon JAK2 inhibitor therapy, both types of mice had equally improved leukocytosis and splenomegaly. Conclusion: TYK2 does not have cooperative effects with JAK2VF upon MPN onset nor in the presence of a JAK2 inhibitor. Classical breakpoint cluster region-Abelson (BCR–ABL)-negative myeloproliferative neoplasms (MPN) includes three main diseases of distinct clinical presentation, namely polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The most recurrent abnormality is a gain-offunction substitution of valine to phenylalanine at position 617 (V617F) in Janus kinase 2 (JAK2) (1). In patients with MPN, clonal expansion of myeloid cells by JAK2 activation results in leukocytosis, hepatosplenomegaly associated with extramedullary hematopoiesis, and constitutional symptoms due to cytokine overproduction. JAK2 inhibitors alleviated these symptoms in clinical trials, and ruxolitinib, the first JAK2 inhibitor approved for the treatment of MPN, is now in widespread clinical use (2, 3). However, in ruxolitinibtreated patients, the therapeutic effects plateau in a few months, and no clear effects on the mutant allele burden have been observed, indicating the presence of resistance to JAK2 inhibitor. As a possible resistance mechanism, it was shown in vitro that JAK2 can form a heterodimer with the nonreceptor tyrosine protein kinase 2 (TYK2) or JAK1 in the presence of JAK2 inhibitor, thereby enhancing downstream signaling (4). In addition, it is unclear whether Janus kinases (i.e. JAK1, JAK2, JAK3, and TYK2) other than JAK2 have cooperative effects such as enhancement or suppression of activated JAK2. If other kinases in addition to JAK2 activate or induce drug resistance, therapies that co-target them might have therapeutic efficacy. In this study, we used a Jak2V617F (Jak2VF)-induced murine MPN model to determine whether TYK2 promoted the severity of MPN in cooperation with JAK2VF, and whether the loss of TYK2 influenced the therapeutic effects of a JAK2 inhibitor.
リポジトリのご案内
Loss of Tyrosine Kinase 2 Does Not Affect the Severity of Jak2V617F-induced Murine Myeloproliferative Neoplasm
