Grant: Project Grant - Priority Announcement: Pediatric Cancer Research

B cells are a specialized subgroup of cells of the immune system that are able to make specific antibodies that can kill bacteria and neutralize viruses are called B cells. They are generated in the bone marrow and are transported via the bloodstream to the spleen and lymph nodes where they undergo a process called affinity maturation to produce highly specific antibodies. This maturation step of B cells takes place in localized areas in the spleen and lymph nodes which are called germinal centers. One particular hallmark of affinity maturation is that it requires the rearrangement and mutation of genes that encode the different part of the antibodies. This process is executed by enzymes such as "Activation induce deaminase" is regulated by so called transcription factors that control gene expression. Although affinity maturation is beneficial for an organism by providing the means for an effective immune response, the genomic reorganization and mutation that it involves bear the risk of generating genetic accidents and aberrant B cells that can give rise to cancers such as B cell lymphoma. One particularly aggressive form of these type of B cell cancers is Burkitt lymphoma, which shows a characteristic chromosomal aberration leading to the activation of the c-MYC transcription factor, the same that normally controls the proliferation of B cell during affinity maturation. A consequence of this aberrant activation of c-MYC is the uncontrolled proliferation and eventually the development of a B cell lymphoma. The present proposal aims to clarify the role of the transcription factors, c-MYC and its co-factor MIZ-1 in the regulation of the normal germinal center reaction, notably the proliferation of B cells and to unveil how the deregulated expression of c-MYC and the c-MYC/MIZ-1 complex is driving the emergence and progression of B cell lymphoma.