We have previously published studies on two tumor suppressive microRNAs, miR-34a and miR-146a, and how they influence B-cell and myeloid development respectively. These two miRNAs lie within central signaling pathways in cancer, and are induced by p53 and NF-kB, respectively. We are therefore very interested to understand if they are dysregulated in B-cell malignancies in particular, which have previously been shown to have disruptions in these pathways. In particular, we are;will define the status of these two miRNAs in a large cohort of clinical lymphoma samples, determine the contribution of these miRNAs to oncogenesis in mouse models, and explore the mechanism of their action using high-throughput sequencing techniques and bioinformatics to define regulated targets and cellular pathways. These studies will likely determine novel interconnections of the p53 and NF-kB pathways and turn up new targets to pursue as potential targets in oncogenesis.
More recently, our independent work has shown that the microRNA miR-146a seems to work through the Early Growth response-1 gene (Egr1). This manuscript was recently published, connecting a tumor suppressive microRNA with a novel pathway. The net result of this deletion of miR-146a was to cause more differentiated B-cell tumors in mice with Myc overexpression. We believe that this effect was exerted via derepression of Egr1 expression which controls the differentiation of B-cells. Depicted below are some of the gene expression parameters that we measured and their normal distribution of expression during the various stages of B-cell maturation.