Glutaminase inhibition as a potential therapeutic strategy in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease and the most prevalent lymphoma in adulthood. Despite the existence of a first-line chemoimmunotherapy regime, approximately one-third of patients remain unresponsive and succumb to the disease, highlighting the need to find novel treatment strategies. In this regard, tumor cells frequently exhibit metabolic reprogramming and become addicted to glutamine, relying on this amino acid and its metabolism to fulfill their bioenergetic and biosynthetic demands, and to maintain homeostasis. This dependency on glutamine becomes a vulnerability that can be exploited therapeutically. Taking this into account, the aim of this study was to investigate the dependence of DLBCL cells on glutaminolysis, as well as exploring the effects and potential of targeting the enzyme glutaminase-1 (GLS1) for the treatment of DLBCL. In the present study, we could show that GLS1 is robustly expressed in multiple DLBCL cell lines. Accordingly, we demonstrated that both pharmacological inhibition and genetic knockdown of GLS1 induce cell death in DLBCL cells independent of their subtype classification and genetic characteristics. Conversely, primary human B-cells remained refractory to this treatment. Interestingly, GLS1 inhibition provoked a stark decrease in common tricarboxylic acid cycle (TCA) intermediaries and, most importantly, significantly increased the levels of cytosolic and mitochondrial reactive oxygen species (ROS). We noticed that the accumulation of ROS upon glutaminase inhibition in DLBCL cells can be partially attributed to the decrease in reduced glutathione (GSH) levels. In this context, we demonstrated that supplementation with a membrane-permeable form of ɑ-ketoglutarate or with thepotent antioxidant ɑ-tocopherol recovered the pool of reduced GSH, attenuated oxidative stress and abrogated the cytotoxicity caused by GLS1 inhibition. Moreover, we examined the effects of combining the GLS1 inhibitor CB-839 with the Bcl-2 inhibitor ABT-199 and observed that this combination not only increases ROS production dramatically, but also induces DLBCL cytotoxicity in a synergistic manner. Collectively, our data defines the crucial role of glutaminolysis for the survival of DLBCL cells through the maintenance of redox homeostasis and highlight the potential of targeting GLS1 and Bcl-2 simultaneously for the treatment of DLBCL patients.Dissertation ist gesperrt bis 04.07.2025

The Paracaspase MALT1 in Cancer

Almost twenty years ago, the importance of the paracaspase MALT1 in antigen receptor-induced NF-κB activation was first described. Since then, several other immune receptors, G-protein-coupled receptors, and receptor tyrosine kinases were identified as relying on MALT1 to induce NF-κB activation. In various hematological malignancies and solid tumors, MALT1 is constitutively activated and drives chronic NF-κB target gene expression. Deregulated MALT1 activity in cancer thus promotes tumor cell survival, proliferation, and metastasis. Since the molecular function of MALT1 partially requires its protease activity, pharmacological targeting of MALT1 may represent a promising anti-cancer strategy. Here, we review the molecular features of MALT1 activation and function as well as the therapeutic potential of MALT1 inhibition in hematological malignancies and solid tumors

Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, but first-line immunochemotherapy fails to produce a durable response in about one-third of the patients. Because tumor cells often reprogram their metabolism, we investigated the importance of glutaminolysis, a pathway converting glutamine to generate energy and various metabolites, for the growth of DLBCL cells. Glutaminase-1 (GLS1) expression was robustly detected in DLBCL biopsy samples and cell lines. Both pharmacological inhibition and genetic knockdown of GLS1 induced cell death in DLBCL cells regardless of their subtype classification, whereas primary B cells remained unaffected. Interestingly, GLS1 inhibition resulted not only in reduced levels of intermediates of the tricarboxylic acid cycle but also in a strong mitochondrial accumulation of reactive oxygen species. Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive reactive oxygen species (ROS) production but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for patients with DLBCL.ISSN:2473-9537ISSN:2473-952