miR-17~92 in B lymphomagenesis

The primary objective of my proposal is to model human B lymphomagenesis in mice using newly developed tools to gain a better understanding of the mechanisms leading to tumor pathogenesis in men. Therefore I will combine targeted gain-of-function mutations in B cells that can be activated at various stages of differentiation and test the impact of their cooperative actions on disease pathogenesis. Post-trancriptional control of gene expression by microRNAs (miRNAs) is emerging as a crucial additional layer of control regulating biological responses in mammalian cells. Individual miRNAs can affect multiple intracellular signalling pathways, although in a highly cell type and context dependent manner. In my project, I will focus on the oncogenic potential of miR-17~92, described to be essential for B cell development and found over-expressed in various human B cell lymphomas. Although it is known from mouse models that miR-17~92 can exert oncogenic potential these miRNAs can not drive tumorigenesis on their own. As tumor development is a multi-step process involving the deregulation of several molecules usually impacting cell death and proliferation, it is likely that the oncogenic miR-17~92 cooperates with other oncogenes during the process of transformation. Therefore, I intend to use B cell restricted conditional mutagenesis of miR-17~92, together with the well-established oncogenes c-Myc or c-Jun. A major shortcoming of currently used transgenic mice is that they over-express a given transgene usually from very early, immature differentiation stages on. This leads in most cases to the development of immature lymphomas and therefore these mouse models can not be translated to the most abundant types of human B cell lymphomas, the majority of which is of mature B cell origin. I intend to circumvent this problem by inducing B cell differentiation stage specific activation of the selected oncogenes, using mouse models generated and available in the host laboratory. To do so, I will use mice containing two conditional gain-of-function alleles, either miR-17~92 and c-Myc or miR-17~92 and c-Jun, and in addition expressing the Cre-recombinase under the control of differentiation specific genes. Conditional activation of the transgenes will be obtained in total B cells from early differentiation stages on by using CD19-cre, in B cells on the transition from immature to mature cells by using CD21-cre and during the germinal center reaction by using C?1- cre. In addition, a key element of my proposal is the attempt to mimic the sporadic nature of somatic cancerogenesis by targeting oncogenic mutations randomly into just a small fraction of B cells by using tamoxifen inducible B cell specific creERT2 mouse strains (CD19-creERT2 and C?1-cre ERT2). My aim is to try to understand whether the initial deregulation of miR-17 ~ 92 in combinations with c-Myc or c- Jun drives a characteristic pattern of further mutations required for full transformation and forcing the transformed cells into a certain B cell lymphoma class. Hopefully, the characterization of aberrant interconnected pathways leading to the development of a certain tumor type, one of the major goals of the host laboratory, will help to develop new and refine existing therapeutic strategies to fight B lymphomagenesis in the human.