Characterization of miR-99a˜125b-2 polycistron in hematopoiesis and leukemogenesis

Introduction: We previously linked high expression of human chromosome 21 (hsa21) encoded miR-125b-2 to the increased risk of children with trisomy 21 (Down Syndrome; DS) to develop acute megakaryoblastic leukemia (DS-AMKL). MiR-125b-2 resides in a tricistronic miRNA cluster harboring miR-99a/let-7c/miR-125b-2.

Methods: Here, we sought to decipher the combined and individual regulatory functions of miR-99˜125 cluster miRNAs during hematopoiesis and leukemic transformation by investigating lentivirally transduced human hematopoietic stem and progenitor cells.

Results: TSS mapping of the miR-99˜125b polycistrons demonstrated simultaneous expression of the pri-miRNA transcripts along with their host gene. Ectopic expression of miR-125b-2 alone or within the polycistron increased colony formation and proliferation of megakaryocytic progenitors (MPs). In contrast overexpression of let-7c and a miR-99a/let-7c construct diminished proliferation in clonogenic assays and liquid culture.

Conclusion: In our observations the polycistrons net effect mostly resembles the miR-125b phenotype. Therefore we speculate that oncogenic miR-125b can surmount the growth-repressive let-7 outcome.