Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

Abstract

<jats:title>Abstract</jats:title> <jats:p>Forkhead box class O1 (FOXO1) acts as a tumor suppressor in solid tumors. The oncogenic phosphoinositide-3-kinase (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 proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell–derived lymphomagenesis.</jats:p>

Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

“…In conclusion, we have identified a previously undiscovered high frequency of FOXO1 mutations in pediatric sporadic and endemic BL. Together with previous findings that FOXO1 is a driver of in DLBCL 15,17 and murine BL-like tumors 19 and may mediate therapeutic resistance, 41 our data further identify the transcription factor FOXO1 as an important factor in pathophysiology of several germinal center-derived B-cell lymphomas. Further exploration of the mechanisms uncoupling FOXO1 from PI3K signaling will aid understanding of BL pathogenesis.…”

“…Mutations affecting the N-terminal AKT recognition motif, including those detected in this study, have been shown to prevent FOXO1 cytoplasmic localization, 17 and indeed Kabrani et al have very recently demonstrated that T24 mutation drives nuclear retention of FOXO1 and thereby cell proliferation and survival in murine PI3K-driven, BL-like tumors carrying acquired FOXO1 mutations. 19 In our study, FOXO1 knockout resulted in a significant decrease in cell proliferation in an endemic BL cell line, supporting an oncogenic function for FOXO1 in human BL as well. Thus, FOXO1 mutation likely represents 1 mechanism by which active PI3K signaling and FOXO1 activity can cooccur in BL cells.…”

“…17 Activating FOXO1 mutations have also been identified in tumors from a murine MYC/ PI3K-driven model of BL and in human BL cell lines. 19 These models demonstrate the role of T24 mutations in uncoupling FOXO1 from BCR/PI3K, driving nuclear localization of FOXO1 protein with subsequent pro-proliferative and pro-survival effects. However, to date, next-generation sequencing (NGS) based studies have identified FOXO1 mutations in only a small proportion of BL patient samples, [20][21][22][23][24] raising the question of how FOXO1 functions in the setting of BCR/PI3K signaling in BL.…”

Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity

“…112 Rapid selection for editing rearrangements in the bone marrow is driven by the need for high-surface immunoglobulin, which activates tonic signals in the phosphatidylinositol-3 kinase (PI3K) pathway that suppresses nuclear FOXO1 transcription factor activity. 121,122 F I G U R E 4 Clonal redemption. 106 cells cycle between a PI3K-active FOXO1-negative light zone state and a PI3K-inactive FOXO1-positive CXCR4 + dark zone state.…”

“…106 119,120 By contrast, Burkitt lymphoma cells establish a perpetual dark zone state where both signals are active by acquiring mutations that increase surface immunoglobulin tonic signaling to PI3K and by mutating FOXO1 to resist inactivation by PI3K. 121,122 F I G U R E 4 Clonal redemption. Antibody displayed as surface antigen receptors on an anergic B cell binds with moderate reactivity to a self-antigen.…”