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Indentifikation von Resistenzmechanismen im diffus großzelligen B Zell Lymphom

Fachliche Zuordnung Hämatologie, Onkologie
Förderung Förderung von 2019 bis 2025
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 417957791
 
Erstellungsjahr 2024

Zusammenfassung der Projektergebnisse

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in the Western world with a media age at diagnosis of >70 years. DLBCL is a clinically and molecularly highly heterogeneous disease. While recent genomic data revealed the identity of numerous molecularly-defined DLBCL clusters, little is known whether this clustering remains stable following genotoxic therapy. It is also largely unclear whether additional mutations are selected under therapeutic pressure. To address these questions, we performed longitudinal whole exome sequencing (WES) and insertional mutagenesis screening. Our data indicate that molecular clustering remains relatively stable in response to anthracyline and/or cisplatin-based frontline and salvage therapy. Moreover, with the exception of TP53, we did not identify any genes that were recurrently altered following exposure to genotoxic damage. Nevertheless, our sequencing and insertional mutagenesis screening in treatment-naïve settings in murine and human DLBCL did reveal interesting hits that we are currently pursuing experimentally. Particularly our dual approach of sequencing and an orthogonal insertional mutagenesis screen almost worked a biofilter, which allowed us to pinpoint genes that scored in all three analyses (human sequencing data, murine sequencing data and piggyBac insertional mutagenesis screening). One of the genes that we are currently pursuing to study its role in DLBCL lymphomagenesis is IRF2BP2, for which we could demonstrate that its deletion led to enhanced NFkB signaling, increased IL-1b secretion and increased sensitivity of DLBCL to IL-1b blockade, both in vitro and in vivo. To further characterize Irf2bp2 in vivo, we generated Cd19Cre/wt;Irf2bp2fl/fl mice. Thus far, one of these animals developed DLBCL at the age of 59 weeks. Analyses of 12 weekold mice in this setting revealed a remarkable increase in GC-B cells, associated with GC output that appeared to be skewed towards memory B cells.

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