Driver genes and pathways in lymphomagenesis

The ultimate goal of the project is to unravel novel avenues for lymphoma patient treatment by the improved characterization of oncogenic pathways and the identification of drugs that interfere with cancer dependencies.

Recently, we generated a preclinical model of GC B cell derived Burkitt lymphoma (BL) by MYC over-expression and PI3K pathway activation (Sander et al., Cancer Cell 2012) and thus identified the PI3K signaling pathway as a promising therapeutic target in BL. However, long latency of tumor development and the monoclonal origin of the tumors pointed towards the need for additional aberrations driving lymphomagenesis. In order to identify these driver genes and pathways, the results of high-throughput screens in mouse and human BL were compared. In the list of candidate genes that were deregulated in both murine and human tumors, we focused on the transcription factor FOXO1. Using various conditional mouse mutants to manipulate FOXO1 activity, we determined its function in the normal GC reaction (Sander et al., Immunity 2015). In the absence of FOXO1 GCs were formed after immunization, but they lacked discernible dark zones (DZs) in which GC B cell clones expanded through massive proliferation. Class switch recombination and the selection of high-affinity antibody mutants were disturbed in these GCs as well. In ongoing projects, we define the function of FOXO1 and other candidates in GC B cell derived lymphomagenesis using CRISPR/Cas9 genome editing and in vitro and in vivo models.

Summary of phenotypic characteristics in the BL-like mouse model (see Sander et al., Cancer Cell 2012). Lymphomas arising after MYC and PI3K activation in GC B cells develop in secondary lymphoid organs (e.g. the Peyer’s patches in the small intestine), show the “starry sky” pattern (HE), have a high mitotic rate (Ki67) and express BL-typical proteins (BCL6, BCL2) and genes (GEP).
© Dr. Sandrine Sander

Immunofluorescence analysis of GCs in spleen sections of wildtype animals (left). FOXO1 (green) is expressed in DZ cells, whereas LZ cells predominantly lack expression of the transcription factor. FACS analysis of control and FOXO1 -/- GCs (right). In the absence of FOXO1 the DZ is missing (see Sander et al., Immunity 2015).
© Dr. Sandrine Sander

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