Role of IRF-4 in the development and maintenance of CLL

Chronic lymphocytic leukemia (CLL) develops in a complex network of immunological interactions. Disease progression is dependent on an interplay between antigen receptor stimulation and T cell support that has relevant parallels with normal immune reactions. The transcription factor IRF-4 has been shown to be a central regulator of B-cell fate in shaped immune environments such as the germinal center (GC). Single nucleotide polymorphism (SNP) analyses point to a role of IRF-4 in the establishment of CLL disease, but the mechanisms involved and the exact role of the gene in modulating the CLL phenotype is elusive. Our preliminary data from human CLL show a potentially relevant role of IRF-4 in modulating proliferative responses within the CLL microenvironment, as well as a relation to prognostic outcome. This proposal aims to define the role of IRF-4 in CLL pathogenesis further by exploiting a well-characterized murine model of CLL, namely the Tcl-1 transgenic (tg) mouse. The role of IRF-4 expression in B-cells during the development and establishment of a CLL clone will be examined by the targeted deletion of IRF-4 in B-cells of Tcl-1 tg mice using a CD19-restricted Cre recombinase system. In parallel, we will also generate an inducible CD19-restricted IRF-4 knockout model to specifically delete IRF-4 in mice with already established CLL disease. Additionally, we propose to introduce an inducible IRF-4 transgene into Tcl-1 tg mice in order to study the influence of IRF-4 overexpression during CLL establishment as well as in already established clonal CLL disease. Ex vivo analysis of cell differentiation, cell death and proliferation will complete the findings in vivo. Finally, the significance of our findings in the murine system will be placed in the context of human CLL where we aim to characterize the relationship between IRF-4 expression and treatment-free survival in patients, study a potential relation to therapy resistance, cell survival and proliferation, and investigate a potential modulation of the immunophenotype.

No additional funding sources recorded.