Format

Send to

Choose Destination
Leukemia. 2014 Jan;28(1):88-97. doi: 10.1038/leu.2013.234. Epub 2013 Aug 9.

BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.

Author information

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.

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.

PMID:
23929215
DOI:
10.1038/leu.2013.234
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center