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.
Highlights
Over the last few decades, a significant improvement in the treatment of children with paediatric B precursor acute lymphoblastic leukaemia (B-precursor ALL) has been achieved, mostly due to the rational use of intensive chemotherapy, and careful clinical and molecular stratification.[1,2,3] Despite this, a proportion of patients still experience disease progression, suggesting a heterogeneous disease pathogenesis
Published data suggest that in a proportion of patients, progressive disease is associated with the presence of bcr/abl fusion transcripts, IKZF1 mutations and deletions, activating JAK mutations, or alterations involving cytokine receptor-like factor 2.6–12 In our previous studies, we have reported an association between apoptotic resistance to ionising radiation (IR)-induced DNA damage in vitro and clinical response in vivo measured by minimal residual disease (MRD).[13,14]
We first observed that the level of expression of bromodomain and extra-terminal (BET) protein BRD4 was uniform in representative ALL cell lines and primary ALL samples
Summary
Over the last few decades, a significant improvement in the treatment of children with paediatric B precursor acute lymphoblastic leukaemia (B-precursor ALL) has been achieved, mostly due to the rational use of intensive chemotherapy, and careful clinical and molecular stratification.[1,2,3] Despite this, a proportion of patients still experience disease progression, suggesting a heterogeneous disease pathogenesis. Published data suggest that in a proportion of patients, progressive disease is associated with the presence of bcr/abl fusion transcripts, IKZF1 mutations and deletions, activating JAK mutations, or alterations involving cytokine receptor-like factor 2.6–12 In our previous studies, we have reported an association between apoptotic resistance to ionising radiation (IR)-induced DNA damage in vitro and clinical response in vivo measured by minimal residual disease (MRD).[13,14] we observed a connection between apoptotic resistance and transcriptional deregulation of multiple pro-survival pathways occurring in a leukaemia-specific manner. We noticed that pharmacological inhibition of individual pro-survival pathways led to heterogeneous responses in vitro and, does not provide a uniform strategy for counteracting apoptotic resistance.[13]
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