Therapy of lymphoma inspired by functional and structural genomics

Wednesday Afternoon Lecture Series Dr. Staudt's laboratory uses genomic technologies to discover molecular subtypes of cancer and develop therapies that target oncogenic regulatory pathways in each subtype. This endeavor is now commonly known as precision medicine and is the direct fruit of the Human Genome Project. The Staudt laboratory has designed the " Lymphochip, " a custom DNA microarray that profiles gene expression in normal lymphocytes as well as in malignant lymphomas and leukemias. His laboratory defined two dominant molecular subtypes of the most common form of non-Hodgkin lymphoma – diffuse large B-cell lymphoma (DLBCL) — and showed that they arise from distinct stages of normal B-cell differentiation, utilize different oncogenic mechanisms, and respond differently to therapy. These subtypes, termed activated B-cell-like (ABC) and germinal center B-cell-like (GCB), are now recognized as distinct diseases. The laboratory has used functional genomics methods (RNAi and CRISPR-Cas9 screens) and structural genomics methods (e.g. cancer gene resequencing) to identify essential regulatory pathways that drive the malignant proliferation and survival of these lymphomas, thereby identifying potential therapeutic targets. For ABC DLBCL, the Staudt laboratory defined a “ chronic active ” form of B-cell receptor (BCR) signaling that activates the pro-survival NF-kB pathway. Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR, ...
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