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Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis
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| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , |
| In: | Blood, 115, 2010, 14, S. 2919-2927 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
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| Schlagwörter: |
| author_facet |
Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. |
|---|---|
| author |
Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. |
| spellingShingle |
Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. Blood Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis Cell Biology Hematology Immunology Biochemistry |
| author_sort |
koppikar, priya |
| spelling |
Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood-2009-04-218842 <jats:title>Abstract</jats:title><jats:p>The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.</jats:p> Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis Blood |
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10.1182/blood-2009-04-218842 |
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American Society of Hematology, 2010 |
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| title |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_unstemmed |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_full |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_fullStr |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_full_unstemmed |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_short |
Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_sort |
efficacy of the jak2 inhibitor incb16562 in a murine model of mplw515l-induced thrombocytosis and myelofibrosis |
| topic |
Cell Biology Hematology Immunology Biochemistry |
| url |
http://dx.doi.org/10.1182/blood-2009-04-218842 |
| publishDate |
2010 |
| physical |
2919-2927 |
| description |
<jats:title>Abstract</jats:title><jats:p>The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.</jats:p> |
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| author | Koppikar, Priya, Abdel-Wahab, Omar, Hedvat, Cyrus, Marubayashi, Sachie, Patel, Jay, Goel, Aviva, Kucine, Nicole, Gardner, Jeffrey R., Combs, Andrew P., Vaddi, Kris, Haley, Patrick J., Burn, Timothy C., Rupar, Mark, Bromberg, Jacqueline F., Heaney, Mark L., de Stanchina, Elisa, Fridman, Jordan S., Levine, Ross L. |
| author_facet | Koppikar, Priya, Abdel-Wahab, Omar, Hedvat, Cyrus, Marubayashi, Sachie, Patel, Jay, Goel, Aviva, Kucine, Nicole, Gardner, Jeffrey R., Combs, Andrew P., Vaddi, Kris, Haley, Patrick J., Burn, Timothy C., Rupar, Mark, Bromberg, Jacqueline F., Heaney, Mark L., de Stanchina, Elisa, Fridman, Jordan S., Levine, Ross L., Koppikar, Priya, Abdel-Wahab, Omar, Hedvat, Cyrus, Marubayashi, Sachie, Patel, Jay, Goel, Aviva, Kucine, Nicole, Gardner, Jeffrey R., Combs, Andrew P., Vaddi, Kris, Haley, Patrick J., Burn, Timothy C., Rupar, Mark, Bromberg, Jacqueline F., Heaney, Mark L., de Stanchina, Elisa, Fridman, Jordan S., Levine, Ross L. |
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| description | <jats:title>Abstract</jats:title><jats:p>The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.</jats:p> |
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| imprint_str_mv | American Society of Hematology, 2010 |
| institution | DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-D161, DE-Zwi2, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1 |
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| spelling | Koppikar, Priya Abdel-Wahab, Omar Hedvat, Cyrus Marubayashi, Sachie Patel, Jay Goel, Aviva Kucine, Nicole Gardner, Jeffrey R. Combs, Andrew P. Vaddi, Kris Haley, Patrick J. Burn, Timothy C. Rupar, Mark Bromberg, Jacqueline F. Heaney, Mark L. de Stanchina, Elisa Fridman, Jordan S. Levine, Ross L. 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood-2009-04-218842 <jats:title>Abstract</jats:title><jats:p>The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.</jats:p> Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis Blood |
| spellingShingle | Koppikar, Priya, Abdel-Wahab, Omar, Hedvat, Cyrus, Marubayashi, Sachie, Patel, Jay, Goel, Aviva, Kucine, Nicole, Gardner, Jeffrey R., Combs, Andrew P., Vaddi, Kris, Haley, Patrick J., Burn, Timothy C., Rupar, Mark, Bromberg, Jacqueline F., Heaney, Mark L., de Stanchina, Elisa, Fridman, Jordan S., Levine, Ross L., Blood, Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis, Cell Biology, Hematology, Immunology, Biochemistry |
| title | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_full | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_fullStr | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_full_unstemmed | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_short | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| title_sort | efficacy of the jak2 inhibitor incb16562 in a murine model of mplw515l-induced thrombocytosis and myelofibrosis |
| title_unstemmed | Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis |
| topic | Cell Biology, Hematology, Immunology, Biochemistry |
| url | http://dx.doi.org/10.1182/blood-2009-04-218842 |