Mechanisms of lymphomagenesis and actionable vulnerabilities in SGK1/TET2 compound-mutant diffuse large B-cell lymphoma

• Applicant: Dr. Benedikt Pelzer
• Subject Area: Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492271820

Therapy of DLBCL is still challenging, especially in relapsed or refractory disease settings. Salvage regimens, including platinum salt-based regimens and consolidating autologous hematopoietic stem cell transplantation, as well as CAR-T cell therapy often do not lead to durable responses. Furthermore, a significant portion of patients is not eligible for these intensive therapy regiments due to frailty.Recent genomic approaches led to characterization of different DLBCL clusters showing distinct pathogenic features and overall survival. One of these groups are SGK1/TET2 compound-mutant DLBCLs, called ST2-DLBCL, harboring truncating mutations in respective genes. Even though they show a better overall survival compared to other DLBCL subgroups, still 20 to 30% of patients succumb to their disease. Unlike in, for example, MCD-cluster DLBCLs, no mechanism for lymphomagenesis has been proposed for ST2-DLBCL. Other mutations assigned to that cluster, as well as GSEA suggest a skewed metabolism to glycolysis, as well as dysregulated signaling in BCR and NF-κB pathways, often in a Ca2+ dependent manner. SGK1- and TET2-loss are predicted to interfere with Ca2+ homeostasis in mitochondria, leading to a rescue of pro-apoptotic signals. Based on these considerations, we propose three specific aims:Aim 1: Development of in vitro and in vivo models for SGK1/TET2 compound-mutant DLBCLs for evaluation of lymphomagenesisAim 2: Identification of actionable targets in SGK1/TET2 compound-mutant DLBCLs through RNA-sequencing, phosphoproteomics and CRISPR/Cas9-loss of function screensAim 3: Evaluation of BCR-induced Ca2+-signaling in SGK1/TET2 compound-mutant DLBCL in vitro. These aims specifically test the hypotheses that 1) CRISPR-engineered cell lines and an autochthonous mouse model of ST2-DLBCL can serve as an experimental platform to elucidate transcriptomic and phosphoproteomic alterations in lymphomagenesis, and 2) ST2-DLBCL may harbor actionable vulnerabilities targetable by precision medicine, due to 3) altered BCR, NF-κB and Ca2+ signaling leading to changes in metabolism and mitochondrial homeostasis. Overall, the proposed experiments will impact the development of new targeted therapies for SGK1/TET2-alterated DLBCL.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ari Melnick