title: Deregulated MIR335 that targets MAPK1 is implicated in poor outcome of paediatric acute lymphoblastic leukaemia.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore City, Singapore.
authors.forename: Junli
authors.initials: J
authors.lastname: Yan
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.forename: Jim L-S
authors.initials: JL
authors.lastname: Tay
authors.forename: Baohong
authors.initials: B
authors.lastname: Lin
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.forename: Grace S
authors.initials: GS
authors.lastname: Koh
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.forename: Joy
authors.initials: J
authors.lastname: Tan
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Chung
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
authors.forename: Shirley K Y
authors.initials: SK
authors.lastname: Kham
authors.forename: Allen E J
authors.initials: AE
authors.lastname: Yeoh
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D012008:Recurrence
chemical_list: C556347:MIRN335 microRNA, human; D035683:MicroRNAs; D011239:Prednisolone; D019950:Mitogen-Activated Protein Kinase 1
keywords: MAPK1; MIR335; clinical outcome; paediatric acute lymphoblastic leukaemia; prednisolone