Klin Padiatr 2016; 228 - A7
DOI: 10.1055/s-0036-1582484

Cooperation between members of the miR-99/100˜125 cluster and PML-RARα in leukemic transformation

M Flasinski 1, S Emmrich 1, O Alejo 1, S Keihani 1, JH Klusmann 1
  • 1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

Introduction: The three human miR-99/100˜125 clusters each containing one miR-99/100, let-7 and miR-125 family member, are processed from one single transcript and are highly expressed in acute promyelocytic leukemia (APL). However, the interaction of miRNAs and PML-RARα during promyelocytic transformation is not well understood.

Results: We established a lentiviral quad-marking system using eGFP, dTomato, Cerulean and E2Crimson to investigate the interaction of three miRNAs and PML-RARα in human hematopoietic stem and progenitor cells in vitro and xenografts in vivo. Lentiviral overexpression of combinations of miR-125b with let-7 and/or miR-99/100, but not single miRNA overexpression, caused an expansion of myeloid progenitors, representing a preleukemic state. Inversely, combinatorial inhibition of the different members of the miR-99/100˜125b tricistron using miRNA sponges and locked nucleic acids was highly efficient to decrease proliferation of APL cell lines.

Conclusion: Our approach will lead to an understanding of the coordinated expression of the tricistronic miRNAs and PML-RARα and uncover their interaction in leukemic transformation.