| The outcome for patients with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, and understanding the pathogenesis of T-ALL is an important step toward developing new therapies. These studies provide new insight into the molecular causes of T-ALL and reveal opportunities for future therapies. For example, the contribution of microRNAs has been unclear. Here, miR-19 was identified as an oncogene in T-ALL and a genome-wide screening approach was employed to reveal the relevant targets for miR- 19's oncogenic activity. MiR-19 regulates BIM (BCL2L11), AMP-activated kinase (PRKAAl) and the phosphatases PTEN and PP2A (PPP2R5E). These targets include key regulators of the PI3K growth and translation program and loss of their expression promotes T-ALL. Expression of miR-19 is transcriptionally controlled by c-MYC. c-MYC is clearly involved in T-ALL, however the causes of MYC activation have remained elusive. Here, deregulated control of MYC translation is identified as a key factor in its overexpression, such that T-ALL cells depend on increased cap-dependent translation. The eIF4A inhibitor Silvestrol was identified as a feasible and safe pharmacological strategy to treat TALL in vivo. Together, these studies have identified key molecular causes of T-ALL development and a new therapeutic strategy that warrants clinical consideration in T-ALL and perhaps other cancers. |
