Members of the miR-99/100˜125 tricistrons cooperatively induce a pre-leukemic phenotype

Introduction: Acute promyelocytic leukemia (APL) is characterized by the accumulation of immature myeloid progenitors. The microRNAs (miRNAs) miR-100 and miR-125b, members of the conserved miR-99/100˜125b tricistrons, are found to be upregulated in APL, although their role in leukemia and myeloid differentiation is yet to be deciphered.

Results: Using a lentiviral Red-Green-Blue (RGB) marking system to investigate genetic interaction as well as eight different miRNA mono-, bi- or tricistronic constructs, we showed that overexpression of miR-125b with miR-99 and/or let-7c leads to an inhibition of myeloid differentiation in vitro and in vivo, inducing a preleukemic phenotype. Global gene expression profiling revealed a core expression signature commonly regulated by miR-125b containing bi-/tricistronic constructs. This core signature is enriched for genes with concordant expression in leukemic stem cells (LSCs) and HSCs.

Conclusion: The tricistron miRNAs form an interaction network, wherein the combined activity of miR-125b with let-7 and/or miR-99/100 family members converged to induce a stem cell signature leading to a pre-leukemic condition.