BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.

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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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Journal

Journal ID (iso-abbrev): Leukemia

Title: Leukemia

ISSN (Electronic): 1476-5551

ISSN (Print): 0887-6924

Publication date (Electronic): Jan 2014

Volume: 28

Issue: 1

Affiliations

[1 ] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.

[2 ] 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.

[3 ] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.

[4 ] Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.

[5 ] 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.

[6 ] 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 Haematology, University of Cambridge, Cambridge, UK.

Article

Publisher Item ID: leu2013234

DOI: 10.1038/leu.2013.234

PubMed ID: 23929215

SO-VID: 86338443-99b6-4242-8dd2-65f05d6cd145

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