Molecular Basis for Progression of Myeloproliferative Neoplasms Induced by JAK2V617F

Molecular Basis for Progression of Myeloproliferative Neoplasms Induced by JAK2V617F Abstract Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are a group of clonal hematologic malignancies characterized by overproduction of myeloid lineage cells. A somatic gain-of-function JAK2V617F mutation has been found in ~95% cases of PV and 50- 60% cases of ET and MF. MF is the deadliest among the MPNs. Patients with PV and ET can also transform to MF. Currently approved JAK2 inhibitors (Ruxolitinib, Fedratinib, Momelotinib) can attenuate constitutional symptoms and splenomegaly, but they do not offer disease remission or significant reduction of bone marrow fibrosis. Furthermore, many patients develop resistance or intolerance to Ruxolitinib therapy after prolonged treatment. This underscores a critical need to better understand the molecular pathogenesis of MPN and identify new therapeutic targets/therapies for MPN, and this is the scientific premise of the proposed research. The deletion of chromosome 20q (del20q) is a common cytogenetic abnormality observed in MPNs, most frequently in MF. However, the identity of the target tumor-suppressor gene(s) within 20q involved in the pathogenesis of MF has remined elusive. We have identified protein tyrosine phosphatase non-receptor type 1 (PTPN1) as a potential tumor suppressor in MPN/MF with del20q abnormality. We have found PTPN1 deletion and its frequent co-association with JAK2V617F mutation in MF. We also have found that PTPN1 deletion increases cell growth and enhances cell signaling in hematopoietic cells expressing JAK2V617F. In addition, we have observed significantly elevated expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in MPN/MF patients and Jak2V617F knock-in mouse models of MPN/MF. We hypothesize that deficiency of PTPN1 and aberrant expression of TIMP-1 may cooperate with JAK2V617F mutation in the development of bone marrow fibrosis and progression of MPN. To test our hypothesis, we have proposed three specific aims. In Aim 1, we will determine the biological and molecular basis for synergy between PTPN1 deficiency and JAK2V617F mutation in the progression of MPN. In Aim 2, we will investigate the role of TIMP-1 and underlying molecular mechanisms in the progression of MPN induced by JAK2V617F. In Aim 3, we will identify and test new therapeutic strategies for MPN/MF. Results from these studies will provide new mechanistic insights into progression of MPN and should lead to new therapeutic approach for treatment of MPN/MF.