BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Hematologic Neoplasms / enzymology
  • Hematologic Neoplasms / metabolism
  • Hematologic Neoplasms / pathology*
  • Humans
  • Janus Kinase 2 / metabolism*
  • Myeloproliferative Disorders / enzymology
  • Myeloproliferative Disorders / metabolism
  • Myeloproliferative Disorders / pathology*
  • Oncogene Proteins / antagonists & inhibitors*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction


  • Oncogene Proteins
  • Janus Kinase 2