BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

Research output: Contribution to journalArticle

External organisations

  • Birmingham Children's Hospital
  • University of Oxford
  • Department of clinical medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland. bashmohamed@gmail.com
  • STRUCTURAL GENOMICS CONSORTIUM

Abstract

Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.

Details

Original languageEnglish
Article numbere126
JournalBlood Cancer Journal
Volume3
Issue number7
Early online date19 Jul 2013
Publication statusPublished - Jul 2013

Keywords

  • ALL, BET proteins, Inhibitor

ASJC Scopus subject areas