Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

FOXO1 acts as a tumor suppressor in solid tumors. The oncogenic PI3K pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B cell derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations which prevent AKT targeting and lock the transcription factor in the nucleus are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development we demonstrate pro-proliferative and anti-apoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B cell derived lymphomagenesis. Isogenic murine BL cell line modified by CRISPR/Cas9 genome editing Genotype definitions: wt+: wild type FOXO1 (mouse) mt+: T24P FOXO1 (mouse) wt-: knockout of wild type FOXO1 (mouse) mt-: knockout of T24P FOXO1 (mouse)