The transcription factor FOXO1 directs germinal center (GC) polarity and supports affinity maturation by modulating immune activation programs in GC B cells. Recurrent somatic mutations targeting FOXO1 in GC-derived B-cell non-Hodgkin lymphomas (B-NHL) are thought to disrupt its negative regulation by PI3K and function as gain-of-function, constitutively active alleles. Herein, we demonstrate that B-NHL FOXO1 mutants are instead hypomorphic alleles encoding proteins with altered transcriptional activities. Analysis of Foxo1 mutant mouse models, engineered cell lines, and primary samples shows that B-NHL FOXO1 mutations induce simultaneous hyperactivation of Stress Activated Protein Kinase -SAPK/JNK and Phosphoinositide 3-kinase -PI3K/AKT signaling pathways and gene expression programs characteristic of GC B cells undergoing positive selection. These alterations confer mutant B cells with a competitive advantage in response to key immune signals, leading to abnormal amplification of GC responses. Moreover, we find that FOXO1 mutant-driven transcriptional programs are prevalent in human B-NHL and predict poor clinical outcomes. These results imply the frequent co-option of GC positive selection programs in the pathogenesis of GC-derived lymphomas.

Citation Format: Mark P. Roberto, Gabriele Varano, Rosa Viñas-Castells, Antony B. Holmes, Rahul Kumar, Pedro Farinha, David W. Scott, David Dominguez-Sola. FOXO1 mutations mimic positive selection signals to promote germinal center B-cell expansion and lymphomagenesis [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-40.