Enhancer priming role of FOXO1 sustains pro-survival BCR signaling in lymphoma

ABSTRACT: Mantle cell lymphoma (MCL) remains incurable requiring new actionable targets. Forkhead Box O1 (FOXO1) exhibits lineage-specific bivalent function as an oncogenic transcription factor that regulates MCL lineage survival function, contrasting with its tumor-suppressor role in other cancer types. Acute degradation of FOXO1-FKBP12F36V by degrader TAG (dTAG) molecules potently induces MCL cell death. Cell cycle restricted degradation of FOXO1 reveals that its function in G1 phase is critical for MCL cell survival. Mechanistically, FOXO1 rapidly reactivates lineage enhancers in the early G1 phase of the cell cycle following the cell division through collaborating with SWI/SNF chromatin remodelers. This interaction facilitates binding and activation of transcription factor PAX5-driven oncogenic MCL lineage gene regulatory networks. Multiomic analysis of FOXO1-dependent transcriptomic changes shows that BCR signaling pathway depends on functional FOXO1 expression. BTK inhibitor combination accelerates G1-specific degradation of FOXO1-caused MCL cell death. Consistently, combined FOXO1 and BTK inhibitors effectively suppress progression of primary MCL cells and MCL xenografts. Our results uncover the molecular networks through which FOXO1 drives MCL lineage survival that can serve as a rationale for a combinatorial targeting of FOXO1 network components with Bruton’s tyrosine kinase inhibitors and explain the mechanism underlying its lineage-restricted oncogenic bivalent activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303985 | GEO | 2025/07/30

REPOSITORIES: GEO