The Significance of MicroRNA-155 in Lymphocytic Malignancy.

Oncogenes and tumor suppressor genes implicated in lymphocytic malignancy mainly encode proteins, but more recent studies have identified specific micro-RNA (miR) molecules that also have an important role in the transformation of lymphocytes. MiRs are non-coding RNA molecules of approximately 22 nucleotides that regulate gene expression by targeting specific mRNAs for silencing or degradation. Certain miR’s, termed oncomiRs, have been shown to play a role in malignant transformation. MiR-155 is one of the first described onco-miRs, with high levels of expression observed in biopsy samples from patients with Hodgkin’s lymphoma, primary mediastinal B cell lymphoma, and diffuse large B cell lymphoma. MiR-155 was demonstrated to have a causal role in B cell transformation in transgenic mice with forced overexpression of miR-155 in the B cell lineage. The transgenic mice develop fatal aggressive B cell malignancies in the first six months of life. The mechanism of miR-155 in lymphocytic transformation remains unclear. Some insight into the physiologic function of miR-155 was gained using mice with a deletion of the gene encoding miR-155. The mice have defects in germinal center formation and in cytokine production by B and T cell lineages. We have used combined gain and loss of function approaches to study the function of miR-155 in T helper cells. Our experiments have demonstrated effects on T helper cell differentiation that are dependent on both the level and the timing of miR-155 expression. The cellular phenotypes we have observed, in combination with computational target prediction have allowed us to identify several promising mRNA targets which are expressed in both T cells and B cells. Currently we are investigating whether any of the target mRNA candidates we have identified contribute to the oncogenic potential of miR-155. We have screened several lymphocyte cell lines for levels of miR-155 expression, and have identified lines in which miR-155 is highly expressed. We are using a loss of function approach to test the dependence of these lines on miR-155 expression. The relative contribution of each candidate target mRNA from our previous studies is being assessed by forced expression of the mRNA in the presence of miR-155 expression and by knockdown in the presence of miR-155 antagonism. Further functional studies and investigation of mRNA targets will help to elucidate both the physiologic role of miR-155 in lymphocytes and its role in lymphocytic malignancy.