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Background  microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 ( KLF4 ), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL.    Methods  Elevated levels of miR-2909 targeted the tumor suppressor gene  KLF4  in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor ( AATF ),  MYC , B-cell lymphoma ( BCL3 ),  P21    CIP   ,  CCND1  and  SP1  in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays.    Results  We identified two novel mutations in  KLF4  in pediatric T-ALL. A mutation in the 3′ untranslated region of the  KLF4  gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered  KLF4  transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant  KLF4  protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene  P21    CIP    confirmed the lack of function of the mutant  KLF4  protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate  KLF4  and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of  KLF4  identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa).    Conclusions  This study identified a novel miR-2909- KLF4  molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.

molecular cancer

miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias