N6-methyladenosine reader IGF2BP2 in T-cell lymphoma

Abstract

Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm, lacking pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methyladenosine (m6A) reader, critically involved in oncogenesis. In this study, we observed consistently high expression of IGF2BP2 across common nodal PTCL subtypes in three independent external cohorts, which was further confirmed in our RNA sequencing (RNA-seq) dataset of 196 patients with newly diagnosed PTCL. Both in vitro and in vivo, IGF2BP2 promoted tumor cell growth and inhibited CD8+ T cell infiltration within the tumor microenvironment. Mechanistically, IGF2BP2 bound to endosome-related genes (RAB4, VPS35, RAB9, and STAM) to maintain their stability, resulting in enhanced endocytic activity and increased internalization of membrane proteins, and ultimately induced tumor cell proliferation and inhibition of CD8+ T cell-mediated tumor cytotoxicity. The relationship between IGF2BP2 and endocytosis-associated genes was confirmed by RNA-seq data of PTCL patients. IGF2BP2 as an upstream regulator of both tumor growth and immune suppression was further demonstrated by patient-derived xenograft models and co-culture system established by tumor samples of PTCL patients and peripheral blood mononuclear cells. Of note, therapeutic targeting of IGF2BP2 with CWI1-2 suppressed endocytosis and impeded tumor growth in both cell lines and patient-derived xenograft models. Collectively, our findings highlight IGF2BP2 as a clinically relevant oncogenic driver in PTCL that integrates tumor-intrinsic growth signals with immune evasion through endocytosis-centered regulation, providing a novel therapeutic rationale for RNA modification-based strategies that concurrently target tumor cells and tumor microenvironment.