Occurrence of sporadic oncogene activation in normal B cells and its implications in lymphomagenesis

Mantle cell lymphoma (MCL) is a B-cell neoplasm with the majority of patients following an aggressive course. Genome-wide maps of genetic aberrations reveal that genetic changes apparently cannot explain all oncogenic lesions fostering MCL formation. In fact, a key oncogenic driver in 90% of MCLs is the aberrant expression of SOX11, which shows no apparent genetic basis, and whose mechanism of early activation remains unknown. 

It is becoming increasingly clear that gene expression levels are influenced by stochastic processes, which may explain the activation of key oncogenes without an apparent underlying genetic mechanism. In line with this, the overall aim of the project is to study the occurrence and combinatorial patterns of sporadic oncogene activation in healthy individuals. To this aim, Beekman’s group will study both gene expression and enhancer activation of MCL-specific oncogenes in normal B-cell fractions at the single-cell level. MCL-specific enhancers of interest and their oncogenic target genes will be selected and their activation status assessed at a single cell resolution. A panoply of bioinformatic tools will also be applied to this project that will yield new conceptual insights into sporadic activation of oncogenes in normal B cells as well as its role in lymphomagenesis.