Deregulated MIR 335 that targets MAPK 1 is implicated in poor outcome of paediatric acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia ( ALL ) is the most common paediatric malignancy. Although 90% of patients are now long‐term survivors, the remaining 10% have poor outcome predominantly due to drug resistance. In this study, we carried out genome‐wide micro RNA (mi RNA ) microarray analysis on diagnostic bone marrow samples to determine mi RNA expression profiles associated with poor outcome in ALL . A reduced expression of MIR 335 was identified as the most significant mi RNA abnormality associated with poor outcome. It is well known that glucocorticoid ( GC ) resistance is one of the major reasons contributing to poor outcome. We show that exogenous expression of MIR 335 in ALL cells increases sensitization to prednisolone‐mediated apoptosis. Moreover, we demonstrate that MAPK 1 is a novel target of MIR 335 , and that MEK / ERK inhibitor treatment enhanced prednisolone‐induced cell death through the activation of BIM ( BCL 2L11). These results provide a possible underlying molecular mechanism to explain the association between reduced MIR 335 with poor clinical outcome, and suggest that approaches to re‐introduce MIR 335 expression or override MAPK 1 activity may offer promising therapeutic strategies in the treatment of ALL .