Understanding mechanisms of drug resistance and clonal evolution in diffuse large B cell lymphoma

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Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in the Western World and represents a major clinical challenge, as only ~60% of patients can be cured by standard frontline chemo-immune therapy. The prognosis of relapsed or refractory patients is dismal, as these patients are difficult to salvage, even when using high-dose chemotherapy, such as BEAM, followed by autologous stem cell support. Through the advent of next generation sequencing technology, the availability of numerous mouse models that faithfully recapitulate important aspects of human DLBCL biology, as well as the possibility to perform large scale genome-wide in vivo insertion mutagenesis screens, we are now in a position to comprehensively profile the genomic events that predict poor response to chemo-immune therapy. More importantly, sequencing of longitudinally obtained tissue samples from mice and men prior to and following the development of (pre-)clinical resistance, allows us to precisely pinpoint genes and pathways that likely mediate resistance. Moreover, a careful inspection of murine and human DLBCL genomes and transcriptomes after the occurrence of resistance may enable us to identify genomic and transcriptomic aberrations that may offer entry routes for targeted therapeutic intervention strategies. Building on these considerations, we have formulated four specific Aims that directly address the above-mentioned questions. Our work program leverages on the large portfolio of tools and technologies that we have assembled in Cologne and Göttingen over the past years. Our specific Aims are as follows:Aim 1: Employ WES to identify recurrent genomic aberrations that are enriched following R-CHOP chemo-immune therapy in patientsAim 2: Employ WES to identify recurrent genomic aberrations that are enriched following R-CHOP chemo-immune therapy in DLBCL GEMMs Aim 3: Perform an in vivo PiggyBac insertional mutagenesis screen to identify mediators of resistance against R-CHOP-like chemo-immune therapyAim 4: Validate candidate resistance-mediating genomic aberrations in vivo, using CRISPR/Cas9 genome editing.