title: Efficacy of vorinostat in a murine model of polycythemia vera.
abstract: The discovery of the JAK2V617F mutation in most patients with Ph-negative myeloproliferative neoplasms has led to the development of JAK2 kinase inhibitors. However, JAK2 inhibitor therapy has shown limited efficacy and dose-limiting hematopoietic toxicities in clinical trials. In the present study, we describe the effects of vorinostat, a small-molecule inhibitor of histone deacetylase, against cells expressing JAK2V617F and in an animal model of polycythemia vera (PV). We found that vorinostat markedly inhibited proliferation and induced apoptosis in cells expressing JAK2V617F. In addition, vorinostat significantly inhibited JAK2V617F-expressing mouse and human PV hematopoietic progenitors. Biochemical analyses revealed significant inhibition of phosphorylation of JAK2, Stat5, Stat3, Akt, and Erk1/2 in vorinostat-treated, JAK2V617F-expressing human erythroleukemia (HEL) cells. Expression of JAK2V617F and several other genes, including GATA1, KLF1, FOG1, SCL, C/EPBα, PU.1, and NF-E2, was significantly down-regulated, whereas the expression of SOCS1 and SOCS3 was up-regulated by vorinostat treatment. More importantly, we observed that vorinostat treatment normalized the peripheral blood counts and markedly reduced splenomegaly in Jak2V617F knock-in mice compared with placebo treatment. Vorinostat treatment also decreased the mutant allele burden in mice. Our results suggest that vorinostat may have therapeutic potential for the treatment of PV and other JAK2V617F-associated myeloproliferative neoplasms.
authors.affiliation: Departments of Pharmacology, State University of New York Upstate Medical University, Syracuse, 13210, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Akada
authors.forename: Saeko
authors.initials: S
authors.lastname: Akada
authors.forename: Ajeet
authors.initials: A
authors.lastname: Gajra
authors.forename: Alicia
authors.initials: A
authors.lastname: Bair
authors.forename: Stephen
authors.initials: S
authors.lastname: Graziano
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hutchison
authors.forename: Golam
authors.initials: G
authors.lastname: Mohi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D051379:Mice; D008817:Mice, Mutant Strains; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2