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Br J Haematol ; 163(1): 93-103, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23888996

ABSTRACT

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 microRNA (miRNA) microarray analysis on diagnostic bone marrow samples to determine miRNA expression profiles associated with poor outcome in ALL. A reduced expression of MIR335 was identified as the most significant miRNA 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 MIR335 in ALL cells increases sensitization to prednisolone-mediated apoptosis. Moreover, we demonstrate that MAPK1 is a novel target of MIR335, and that MEK/ERK inhibitor treatment enhanced prednisolone-induced cell death through the activation of BIM (BCL2L11). These results provide a possible underlying molecular mechanism to explain the association between reduced MIR335 with poor clinical outcome, and suggest that approaches to re-introduce MIR335 expression or override MAPK1 activity may offer promising therapeutic strategies in the treatment of ALL.


Subject(s)
MicroRNAs/genetics , Mitogen-Activated Protein Kinase 1/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Cell Line, Tumor , Child , Child, Preschool , Computational Biology/methods , Drug Resistance, Neoplasm/genetics , Female , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Leukemic , Genetic Vectors/genetics , Humans , Lentivirus/genetics , MAP Kinase Signaling System/drug effects , Male , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisolone/pharmacology , Prednisolone/therapeutic use , Prognosis , Recurrence
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