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BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.
Wyspianska, B S; Bannister, A J; Barbieri, I; Nangalia, J; Godfrey, A; Calero-Nieto, F J; Robson, S; Rioja, I; Li, J; Wiese, M; Cannizzaro, E; Dawson, M A; Huntly, B; Prinjha, R K; Green, A R; Gottgens, B; Kouzarides, T.
Afiliação
  • Wyspianska BS; Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
  • Bannister AJ; Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
  • Barbieri I; Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
  • Nangalia J; 1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
  • Godfrey A; 1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
  • Calero-Nieto FJ; Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Robson S; Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
  • Rioja I; Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • Li J; 1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
  • Wiese M; 1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Cannizzaro E; 1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Dawson MA; 1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [3] Addenbrooke's Hospital, Department of Haemato
  • Huntly B; Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Prinjha RK; Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • Green AR; 1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
  • Gottgens B; Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • Kouzarides T; Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
Leukemia ; 28(1): 88-97, 2014 Jan.
Article em En | MEDLINE | ID: mdl-23929215
ABSTRACT
Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Oncogênicas / Neoplasias Hematológicas / Janus Quinase 2 / Transtornos Mieloproliferativos Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Oncogênicas / Neoplasias Hematológicas / Janus Quinase 2 / Transtornos Mieloproliferativos Idioma: En Ano de publicação: 2014 Tipo de documento: Article