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Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.
Wu, Shuo-Chieh; Li, Loretta S; Kopp, Nadja; Montero, Joan; Chapuy, Bjoern; Yoda, Akinori; Christie, Amanda L; Liu, Huiyun; Christodoulou, Alexandra; van Bodegom, Diederik; van der Zwet, Jordy; Layer, Jacob V; Tivey, Trevor; Lane, Andrew A; Ryan, Jeremy A; Ng, Samuel Y; DeAngelo, Daniel J; Stone, Richard M; Steensma, David; Wadleigh, Martha; Harris, Marian; Mandon, Emeline; Ebel, Nicolas; Andraos, Rita; Romanet, Vincent; Dölemeyer, Arno; Sterker, Dario; Zender, Michael; Rodig, Scott J; Murakami, Masato; Hofmann, Francesco; Kuo, Frank; Eck, Michael J; Silverman, Lewis B; Sallan, Stephen E; Letai, Anthony; Baffert, Fabienne; Vangrevelinghe, Eric; Radimerski, Thomas; Gaul, Christoph; Weinstock, David M.
Afiliação
  • Wu SC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Li LS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Kopp N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Montero J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Chapuy B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Yoda A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Christie AL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Liu H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Christodoulou A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • van Bodegom D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • van der Zwet J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Layer JV; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Tivey T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Lane AA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Ryan JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Ng SY; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • DeAngelo DJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Stone RM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Steensma D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Wadleigh M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Harris M; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Mandon E; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Ebel N; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Andraos R; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Romanet V; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Dölemeyer A; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Sterker D; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Zender M; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Rodig SJ; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Murakami M; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Hofmann F; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Kuo F; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Eck MJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Silverman LB; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Sallan SE; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Baffert F; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Vangrevelinghe E; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Radimerski T; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • Gaul C; Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. Electronic address: christoph.gaul@novartis.com.
  • Weinstock DM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: dweinstock@partners.org.
Cancer Cell ; 28(1): 29-41, 2015 Jul 13.
Article em En | MEDLINE | ID: mdl-26175414
A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzimidazóis / Dexametasona / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Janus Quinase 2 / Leucemia-Linfoma Linfoblástico de Células Precursoras / Aminopiridinas / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzimidazóis / Dexametasona / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Janus Quinase 2 / Leucemia-Linfoma Linfoblástico de Células Precursoras / Aminopiridinas / Antineoplásicos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article