Efficacy of vorinostat in a murine model of polycythemia vera
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,...
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| Veröffentlicht in: | Blood 2012-04, Vol.119 (16), p.3779-3789 |
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| creator | Akada, Hajime Akada, Saeko Gajra, Ajeet Bair, Alicia Graziano, Stephen Hutchison, Robert E. Mohi, Golam |
| description | 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. |
| doi_str_mv | 10.1182/blood-2011-02-336743 |
| format | Article |
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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.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-02-336743</identifier><identifier>PMID: 22408262</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Apoptosis - physiology ; Biological and medical sciences ; Cell Cycle Checkpoints - drug effects ; Cell Cycle Checkpoints - physiology ; Cell Division - drug effects ; Cell Division - physiology ; Disease Models, Animal ; Diseases of red blood cells ; Erythroblasts - cytology ; Erythroblasts - drug effects ; Erythroblasts - physiology ; Gene Knock-In Techniques ; Hematologic and hematopoietic diseases ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - drug effects ; Hematopoietic Stem Cells - physiology ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Hydroxamic Acids - pharmacology ; Janus Kinase 2 - genetics ; Janus Kinase 2 - metabolism ; K562 Cells ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Mice ; Mice, Mutant Strains ; Myeloid Neoplasia ; Polycythemia Vera - drug therapy ; Polycythemia Vera - metabolism ; Polycythemia Vera - pathology ; Polycythemias ; Treatment Outcome ; Vorinostat</subject><ispartof>Blood, 2012-04, Vol.119 (16), p.3779-3789</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2012 by The American Society of Hematology 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c559t-414ee7a6c10b6ecaf559d38214aa2c2038f74a5094a667841b4317981e22ce7c3</citedby><cites>FETCH-LOGICAL-c559t-414ee7a6c10b6ecaf559d38214aa2c2038f74a5094a667841b4317981e22ce7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25802154$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22408262$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akada, Hajime</creatorcontrib><creatorcontrib>Akada, Saeko</creatorcontrib><creatorcontrib>Gajra, Ajeet</creatorcontrib><creatorcontrib>Bair, Alicia</creatorcontrib><creatorcontrib>Graziano, Stephen</creatorcontrib><creatorcontrib>Hutchison, Robert E.</creatorcontrib><creatorcontrib>Mohi, Golam</creatorcontrib><title>Efficacy of vorinostat in a murine model of polycythemia vera</title><title>Blood</title><addtitle>Blood</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Cycle Checkpoints - physiology</subject><subject>Cell Division - drug effects</subject><subject>Cell Division - physiology</subject><subject>Disease Models, Animal</subject><subject>Diseases of red blood cells</subject><subject>Erythroblasts - cytology</subject><subject>Erythroblasts - drug effects</subject><subject>Erythroblasts - physiology</subject><subject>Gene Knock-In Techniques</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - drug effects</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Janus Kinase 2 - genetics</subject><subject>Janus Kinase 2 - metabolism</subject><subject>K562 Cells</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Myeloid Neoplasia</subject><subject>Polycythemia Vera - drug therapy</subject><subject>Polycythemia Vera - metabolism</subject><subject>Polycythemia Vera - pathology</subject><subject>Polycythemias</subject><subject>Treatment Outcome</subject><subject>Vorinostat</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EouXxBwhlwzIwHjuPLkBCiJeExAbW1tSZgFESV3ZaqX9PSqGFDStrPPfemTlCnEg4l7LEi2njfZUiSJkCpkrlhVY7YiwzLFMAhF0xBoA81ZNCjsRBjB8AUivM9sUIUUOJOY7F5W1dO0t2mfg6WfjgOh976hPXJZS086HmpPUVN6v-zDdLu-zfuXWULDjQkdirqYl8_P0eite725ebh_Tp-f7x5voptVk26VMtNXNBuZUwzdlSPfxWqkSpidAiqLIuNGUw0ZTnRanlVCtZTErJiJYLqw7F1Tp3Np-2XFnu-kCNmQXXUlgaT8787XTu3bz5hVFKZcOgIUCvA2zwMQauN14JZoXTfOE0K5wG0KxxDrbT33M3ph9-g-DsW0DRUlMH6qyLW11WAspMbw_ggdLCcTDROu4sVy6w7U3l3f-bfAJAfZPy</recordid><startdate>20120419</startdate><enddate>20120419</enddate><creator>Akada, Hajime</creator><creator>Akada, Saeko</creator><creator>Gajra, Ajeet</creator><creator>Bair, Alicia</creator><creator>Graziano, Stephen</creator><creator>Hutchison, Robert E.</creator><creator>Mohi, Golam</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20120419</creationdate><title>Efficacy of vorinostat in a murine model of polycythemia vera</title><author>Akada, Hajime ; Akada, Saeko ; Gajra, Ajeet ; Bair, Alicia ; Graziano, Stephen ; Hutchison, Robert E. ; Mohi, Golam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c559t-414ee7a6c10b6ecaf559d38214aa2c2038f74a5094a667841b4317981e22ce7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Biological and medical sciences</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Cycle Checkpoints - physiology</topic><topic>Cell Division - drug effects</topic><topic>Cell Division - physiology</topic><topic>Disease Models, Animal</topic><topic>Diseases of red blood cells</topic><topic>Erythroblasts - cytology</topic><topic>Erythroblasts - drug effects</topic><topic>Erythroblasts - physiology</topic><topic>Gene Knock-In Techniques</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hematopoietic Stem Cells - cytology</topic><topic>Hematopoietic Stem Cells - drug effects</topic><topic>Hematopoietic Stem Cells - physiology</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Janus Kinase 2 - genetics</topic><topic>Janus Kinase 2 - metabolism</topic><topic>K562 Cells</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Myeloid Neoplasia</topic><topic>Polycythemia Vera - drug therapy</topic><topic>Polycythemia Vera - metabolism</topic><topic>Polycythemia Vera - pathology</topic><topic>Polycythemias</topic><topic>Treatment Outcome</topic><topic>Vorinostat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akada, Hajime</creatorcontrib><creatorcontrib>Akada, Saeko</creatorcontrib><creatorcontrib>Gajra, Ajeet</creatorcontrib><creatorcontrib>Bair, Alicia</creatorcontrib><creatorcontrib>Graziano, Stephen</creatorcontrib><creatorcontrib>Hutchison, Robert E.</creatorcontrib><creatorcontrib>Mohi, Golam</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akada, Hajime</au><au>Akada, Saeko</au><au>Gajra, Ajeet</au><au>Bair, Alicia</au><au>Graziano, Stephen</au><au>Hutchison, Robert E.</au><au>Mohi, Golam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy of vorinostat in a murine model of polycythemia vera</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-04-19</date><risdate>2012</risdate><volume>119</volume><issue>16</issue><spage>3779</spage><epage>3789</epage><pages>3779-3789</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><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.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22408262</pmid><doi>10.1182/blood-2011-02-336743</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Apoptosis - physiology Biological and medical sciences Cell Cycle Checkpoints - drug effects Cell Cycle Checkpoints - physiology Cell Division - drug effects Cell Division - physiology Disease Models, Animal Diseases of red blood cells Erythroblasts - cytology Erythroblasts - drug effects Erythroblasts - physiology Gene Knock-In Techniques Hematologic and hematopoietic diseases Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - drug effects Hematopoietic Stem Cells - physiology Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - pharmacology Janus Kinase 2 - genetics Janus Kinase 2 - metabolism K562 Cells Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Mice Mice, Mutant Strains Myeloid Neoplasia Polycythemia Vera - drug therapy Polycythemia Vera - metabolism Polycythemia Vera - pathology Polycythemias Treatment Outcome Vorinostat |
| title | Efficacy of vorinostat in a murine model of polycythemia vera |
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