Abstract A028: Targeting eIF4A1 reveals crosstalk between BCR signaling and translation in aggressive B-cell lymphoma

Abstract

Chronic B-cell receptor (BCR) signaling is a central driver of aggressive B-cell lymphomas, reinforcing oncogenic survival and proliferation programs; yet the mechanisms by which these signaling outputs are sustained at the level of protein synthesis remain to be fully elucidated. We hypothesized that selective mRNA translation mediated by eIF4A1 acts as a key regulator of BCR-driven oncogenic programs and represents a therapeutically actionable vulnerability. The RNA helicase eIF4A1 is a core component of cap-dependent translation initiation that facilitates ribosome loading on transcripts with structured 5′ untranslated regions. Analysis of lymphoma datasets and primary tumor samples demonstrates that eIF4A1 expression is elevated in diffuse large B-cell lymphoma relative to normal B cells and is associated with adverse clinical outcomes, supporting its disease relevance. Consistent with this expression pattern and its role in regulating translation of structured mRNAs, eIF4A1 activity sustains the expression of key oncogenic drivers, including MYC and survival-associated programs linked to BCR/NF-κB signaling, positioning it as a link between oncogenic signaling and protein synthesis. Supporting this role, functional genomic analyses further indicate that lymphoma cells rely on eIF4A1 activity to maintain oncogenic protein expression. To exploit this therapeutic vulnerability, we developed RocA-independent small-molecule inhibitors of eIF4A1, RBF197, and RBF208 that impair helicase-mediated unwinding of structured mRNAs. Pharmacologic inhibition of eIF4A1 suppresses lymphoma cell proliferation and clonogenicity, accompanied by reduced expression of oncogenic drivers including MYC, BCL2, and CCND1, while maintaining relative selectivity for malignant B cells. In orthotopic lymphoma models, RBF197 achieves target engagement and induces significant tumor growth inhibition with favorable pharmacokinetic properties. To further link these observations to oncogenic signaling networks, we evaluated independent models of B-cell activation and lymphoma, where BCR engagement is associated with enhanced translational output and enrichment of eIF4A1-responsive programs, whereas inhibition of eIF4A1 produces reciprocal suppression of these gene signatures. Combinatorial profiling across nodes of the BCR signaling cascade reveals pathway-selective interactions with eIF4A1 inhibition, indicating functional convergence between oncogenic signaling and translational control. Complementary perturbation studies further support functional interplay, whereas BCR activation augments protein translation and inhibition of BCR-associated signaling attenuates eIF4A1-dependent translational output. Ongoing ribosome profiling studies aim to refine these eIF4A1-dependent translational programs. Collectively, these findings position eIF4A1 as a key regulator linking oncogenic signaling to protein synthesis in aggressive lymphoma and highlight the BCR-translation axis as a therapeutically actionable vulnerability.