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Published on: October 14, 2016
Efficacy of vorinostat in a murine model of polycythemia vera
Hajime Akada1, Saeko Akada, Ajeet Gajra
1Departments of Pharmacology, State University of New York Upstate Medical University, Syracuse, 13210, USA.
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.
Insights
Vorinostat, a histone deacetylase inhibitor, effectively reduced proliferation and induced apoptosis in cells with the JAK2V617F mutation. This drug normalized blood counts and reduced spleen size in a polycythemia vera mouse model, suggesting therapeutic potential.
Area of Science:
- Oncology
- Hematology
- Molecular Biology
Background:
- The JAK2V617F mutation is prevalent in Philadelphia chromosome-negative myeloproliferative neoplasms.
- JAK2 kinase inhibitors show limited efficacy and significant toxicity in clinical trials.
- There is a need for novel therapeutic strategies for JAK2V617F-associated myeloproliferative neoplasms.
Purpose of the Study:
- To investigate the therapeutic potential of vorinostat, a histone deacetylase inhibitor, in preclinical models of JAK2V617F-driven myeloproliferative neoplasms.
- To evaluate the effects of vorinostat on JAK2V617F-expressing cells and hematopoietic progenitors.
- To assess the in vivo efficacy of vorinostat in a polycythemia vera (PV) animal model.
Main Methods:
- In vitro studies using cells expressing JAK2V617F.
- Assessment of proliferation, apoptosis, and signaling pathway inhibition.
- Analysis of gene expression changes.
- In vivo studies using Jak2V617F knock-in mice with polycythemia vera.
Main Results:
- Vorinostat significantly inhibited proliferation and induced apoptosis in JAK2V617F-expressing cells.
- Vorinostat suppressed phosphorylation of JAK2, Stat5, Stat3, Akt, and Erk1/2.
- In vivo, vorinostat treatment normalized peripheral blood counts, reduced splenomegaly, and decreased the mutant allele burden in mice.
Conclusions:
- Vorinostat demonstrates potent anti-proliferative and pro-apoptotic effects against JAK2V617F-expressing cells.
- Vorinostat effectively targets key signaling pathways implicated in myeloproliferative neoplasms.
- Vorinostat shows significant therapeutic promise for treating polycythemia vera and other JAK2V617F-associated myeloproliferative neoplasms.
