The myeloproliferative neoplasmss (MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a group of hematologic malignancies characterized by excessive production of myeloid lineage cells. A somatic point mutation (V617F) in the JAK2 tyrosine kinase has been detected in most patients with PV and 50-60% patients with ET and PMF. Additional mutations in the thrombopoietin receptor MPL (MPLW515L, MPLW515K) have been found in 5-10% cases of ET and PMF. At present, there is no curative therapy for these MPNs. Recently, a number of JAK2 inhibitors have been developed and undergoing Phase I clinical trials. Although there is considerable enthusiasm for JAK2 inhibitor for these disorders, there are also a number of important concerns. There is evidence that JAK2V617F- negative acute myeloid leukemia occurs frequently in patients with a JAK2V617F-positive MPN, raising the possibility that JAK2 inhibitor therapy might increase the risk of leukemic transformation. Moreover, drug resistance is likely to emerge in some patients treated with JAK2 inhibitors. Therefore, identifying additional therapies targeting JAK2V617F or MPLW515L or critical pathways downstream of JAK2V617F/MPLW515L would be beneficial for the treatment of MPNs. In preliminary studies, we have observed that histone deacetylase (HDAC) inhibitor vorinostat selectively inhibits JAK2V617F expression and induces apoptosis in hematopoietic cells expressing JAK2V617F or MPLW515L. We have generated a knock-in mouse model of JAK2V617F-evoked MPN. We will this knock-in mouse model of JAK2V617F and retroviral bone marrow transplant model of MPLW515L to test the efficacy of HDAC inhibitor vorinostat in treating MPNs. The molecular mechanism of anti-cancer activity of vorinostat in MPN will also be determined. The results of these studies will lay the groundwork for Phase I and II clinical trials involving HDAC inhibitor vorinostat in the treatment of MPNs.
The proposed studies will evaluate the efficacy of histone deacetylase (HDAC) inhibitor vorinostat in pre- clinical models of MPNs, and identify the bio-marker for vorinostat therapy in MPNs. The data generated from these studies will lay the groundwork for Phase I and II clinical trials of vorinostat in MPNs.
|Akada, Hajime; Akada, Saeko; Gajra, Ajeet et al. (2012) Efficacy of vorinostat in a murine model of polycythemia vera. Blood 119:3779-89|