BET protein inhibition shows efficacy against JAK2V617F driven neoplasms
Nature Publishing Group
MetadataShow full item record
Wyspiańska, B., Bannister, A., Barbieri, I., Nangalia, J., Godfrey, A., Calero-Nieto, F., Robson, S., et al. (2013). BET protein inhibition shows efficacy against JAK2V617F driven neoplasms. Leukemia, 28 88-97. https://doi.org/10.1038/leu.2013.234
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 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 down regulated by I-BET151 was LMO2, an important oncogenic regulator of ematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon 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 overlapping, 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.
JAK2V617F, BET proteins, LMO2, Myeloproliferative Neoplasms
The Kouzarides laboratory was supported by Cancer Research UK, Leukaemia and Lymphoma Research, GlaxoSmithKline and BBSRC. The Green laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Gottgens laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Huntly laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. M. A Dawson, E Cannizzaro and M. Wiese are funded by the Wellcome Trust Beit Fellowship.
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (097922/Z/11/Z)
Leukemia & Lymphoma Society (7001-12)
Cancer Research UK (12765)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (079249/Z/06/H)
External DOI: https://doi.org/10.1038/leu.2013.234
This record's URL: https://www.repository.cam.ac.uk/handle/1810/245323