BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms

B. S. Wyspiańska, Andrew J. Bannister, Isaia Barbieri, J. Nangalia, A. Godfrey, F. J. Calero-nieto, S. Robson, I. Rioja, J. Li, M. Wiese, E. Cannizzaro, M. A. Dawson, B. J. P. Huntly, Rab K. Prinjha, A. R. Green, B. Gottgens, Tony Kouzarides

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)88-97
Number of pages10
Issue number1
Early online date6 Sept 2013
Publication statusPublished - 1 Jan 2014


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