Klin Padiatr 2009; 221 - A51
DOI: 10.1055/s-0029-1222671

Oncogenic Potential of miR-125b-2 and its Target Genes in Normal and Malignant Hematopoesis

T Pushpanathan 1, 6, J Klusmann 1, 6, Z Li 2, 5, K Böhmer 1, FJ Godinho 4, 5, ML Koch 1, SH Orkin 2, 3, 4, 5, D Reinhardt 1
  • 1Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany
  • 2Harvard Medical School and Harvard Stem Cell Institute, Cambridge, MA, USA
  • 3Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA
  • 4Howard Hughes Medical Institute, Boston, MA, USA
  • 5Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA
  • 6These authors contributed equally to this work

Children with Down Syndrome (DS) have increased risk for acute myeloid leukemia (AML), suggesting the presence of an additional copy of chromosome 21 is potentially oncogenic. We previously showed upregulation of chromosome 21 encoded miR-125b-2 in DS-AMKL. MiR-125b-2 increases the proliferation rate of hematopoietic stem and progenitor cells (HSPCs) while repressing myeloid differentiation, both in the murine and human system. Via integrative analyses of the transcriptome we identified a set of miR-125b-2 target genes in hematopoietic cells. Using Gene Set Enrichment Analysis (GSEA) we confirmed the downregulation of the target genes in those patients highly expressing miR-125b. DICER1, LIFR and ST18 were proven to be direct targets of miR-125b-2 as assayed by luciferase reporter assays. QRT-PCR on cell lines transduced to overexpress miR-125b-2 showed decreased mRNA expression of those genes. Thus, our study supports a role of miR-125b-2 as an oncomiR in the pathogenesis of trisomy 21-associated AML and provides evidence that miR-125b-2 exerts its oncogenic potential by blocking post-transcriptional miRNA processing through repression of DICER1 and by inhibiting tumor suppressors like ST18 and LIF-R.