Mutations in IRF4 in Immunodeficiency and Cancer

Host: Professor Ian Cockburn

Abstract

IRF4 is a transcription factor with crucial roles in the differentiation of many haematopoietic cells. In B cells, IRF4 has non-redundant roles in the formation of germinal centres and the terminal differentiation of B cells into antibody secreting plasma cells. We recently identified a mutation in the DNA-binding domain of IRF4 in multiple patients with primary immunodeficiency. Our analysis revealed that the mutation causes disease through a complex mix of loss-, gain- and novel functions. In mice, the same mutation also causes an expansion of the B1 cell subsets of B cells and eventually the development of a CLL-like disease.

Other mutations in the DNA-binding domain of IRF4 have also been found in many haematopoietic cancers. Interestingly, each malignancy is associated with a limited set of mutations, strongly suggesting a specific effect of each of the mutations. This is supported by our analysis of novel mouse models carrying some of the cancer-associated mutations which showed that each mutation causes a very specific effect on the development of B cells and the formation of the germinal centres. These mice provide a unique tool to dissect different aspects of B- and T- cell activation and the formation of germinal centres.

Biography

Associate Professor Anselm Enders received his Doctor of Medicine at the University of Freiburg. Following two years of training in paediatric immunology at the Children’s University Hospital in Freiburg, he joined the group of Professor Chris Goodnow at The John Curtin School of Medical Research for postdoctoral training. In 2012, he was awarded an NHMRC Career Development Fellowship. His work focuses on B cell development and how mutations affecting B cell development or function cause primary immunodeficiencies.