The role of MGA in the pathogenesis of Richter Transformation

About This Grant

Project summary/abstract Richter Transformation (RT) is an aggressive, therapy-refractory large cell lymphoma that arises in up to 10% of patients with chronic lymphocytic leukemia (CLL). RT represents a major unmet need in CLL management, as patients are largely refractory to existing therapies and have a median overall survival of less than 12 months. Immunotherapies, including immune checkpoint blockade (ICB), have shown promise in RT, but responses often display limited duration. The objective of this study is to elucidate the molecular function of the MAX dimerization protein MGA, a gene that is disrupted by inactivating mutations leading to loss-of-function (LOF) in ~29% of RT cases. Our long-term goal is to improve the efficacy of immunotherapy-based combination treatments for this currently incurable malignancy, tailored to the molecular characteristics of patients. We hypothesize that MGALOF regulates tumor cell fitness by controlling growth programs and inflammatory signaling, thereby promoting B-cell clonal expansion and immune evasion. This hypothesis is supported by preliminary data showing that MGA-LOF leads to de-repression of transcription factors involved in proliferation and inflammatory cytokine production in both human tumors and murine models. In murine models faithful to the CLL-to-RT progression, Mga-LOF drives clonal selection of malignant B cells and promotes the formation of a PD-1+ T-cell rich tumor microenvironment (TME). In this study, we will pursue two specific aims: 1) define the mechanisms through which Mga-LOF favors B-cell fitness during the CLL transformation into RT; 2) determine how Mga-LOF driven inflammatory signaling rewires the RT-TME, predisposing Mga-LOF RT to anti-PD-1 ICB-based combination therapies. These questions will be addressed through integrated studies of faithful murine models of the CLL-to- RT evolution, isogenic human cell lines, and genetically annotated patient samples collected longitudinally during CLL progression or at time of RT. As primary RT samples are generally scarce and mostly available as fixed, non-viable, tissue, they preclude ex vivo manipulation and longitudinal functional studies. Our novel immunocompetent murine models provide a necessary and physiologically relevant platform to investigate the molecular mechanisms underlying the stepwise CLL-to-RT evolution, enabling the preclinical evaluation of novel therapeutic strategies. We have assembled a multidisciplinary team to support this work, including experts in computational biology (Landau), stem cell biology and epigenetics (Apostolou), and tumor immunology (Zappasodi). Collaborations with clinicians (Furman, Thompson, Inghirami, Parry) will provide access to genetically annotated patient specimens and spatial transcriptomics datasets from ongoing immunotherapy clinical trials. This research is significant because it will reveal critical biological mechanisms underlying CLL transformation and provide a preclinical foundation for personalized therapies for RT patients.