The Dose-Dependent Effects of Microrna-155 in Acute Myeloid Leukemia

MicroRNAs are a class of non-coding, regulatory RNAs that control several critical cellular processes. Subsets of microRNAs are dysregulated in cancer, and can act as oncogenes or tumour suppressors.

MicroRNA-155 (miR-155) has a well-established role as an oncogene in B cell lymphoma but has a more enigmatic role in acute myeloid leukemia (AML), in which there is evidence that miR-155 may promote or repress the development and progression of AML. We have used enforced expression of miR-155 in murine AML cell lines and AML models to explore the biology of miR-155 in AML.

We show that the capacity of miR-155 to promote or repress the ability of AML cells to form colonies and to proliferate is dependent on miR-155 expression levels. Enforced high expression of miR-155 in AML cell lines results in reduced proliferation and colony formation. However, critical long-term assays of cells transduced with miR-155 resulted in selection in favour of an intermediate miR-155 expression level accompanied by a restoration in clonogenic potential. In vivo, enforced expression of miR-155 in murine AML models showed no differences in disease latency compared to controls, but resulted in an increased tumour burden. Most interestingly, RNA-Sequencing analysis demonstrated that the contrasting levels of miR-155 regulate a substantially different set of gene targets, with downstream consequences on transcription that are consistent with the contrasting effects of high and intermediate miR-155 levels. The intermediate levels of miR-155 we observe are the same as that seen in human AML, whereas the high levels of miR-155 have a completely different inflammatory counterpart. Our data shows that that the levels of miR-155 powerfully influences that gene targets it controls and the resultant phenotypes observed. MiR-155 expressed within a specific range promotes AML disease progression.