—  SOCIETY FOR HEMATOPATHOLOGY   — Molecular Pathogenesis of Diffuse Large Cell Lymphoma Riccardo Dalla-Favera College of Physicians and Surgeons Columbia University New York, NY B cell derived diffuse large cell lymphoma (DLCL) derive from the germinal center (GC), the structure where naïve B cells encounter the antigen, undergo Immunoglobulin (Ig) V region somatic hypermutation (SH) and class switch recombination (CSR), and are selected to become memory B cells or plasma cells. SH and CSR mechanisms are involved in the generation of specific chromosomal translocations, which contribute to the pathogenesis of DLCL by deregulating the expression of oncogenes like BCL2 and BCL6. New findings indicate that: i) the somatic hypermutation mechanism is aberrantly activated in >50% of DLCL leading to the mutation of multiple proto-oncogenes and, possibly, to the generation of chromosomal translocations; ii) the BCL6 proto-oncogene, which is normally downregulated by CD40 signaling, becomes constitutively expressed in the majority DLCL cases; iii) the function of BCL6 is controlled by three distinct pathways that can be modulated for therapeutic purposes.