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

摘要

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