title: BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia.
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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: D
authors.initials: D
authors.lastname: Da Costa
authors.forename: A
authors.initials: A
authors.lastname: Agathanggelou
authors.forename: T
authors.initials: T
authors.lastname: Perry
authors.forename: V
authors.initials: V
authors.lastname: Weston
authors.forename: E
authors.initials: E
authors.lastname: Petermann
authors.forename: A
authors.initials: A
authors.lastname: Zlatanou
authors.forename: C
authors.initials: C
authors.lastname: Oldreive
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.forename: G
authors.initials: G
authors.lastname: Stewart
authors.forename: J
authors.initials: J
authors.lastname: Longman
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Kearns
authors.forename: S
authors.initials: S
authors.lastname: Knapp
authors.forename: T
authors.initials: T
authors.lastname: Stankovic