Dysregulated KMT2D mutant targeting immunogenic rewiring to overcome epigenetic entropy promotes follicular lymphomagenesis.

Abstract

Background: Epigenetic modifier factors in B cell lymphomas often harbor loss-of-function mutations. Mutations occurring in the histone-lysine methyltransferase 2D (KMT2D) gene are the pivotal chromatin-modifying hallmarks of follicular lymphoma (FL) subsets, however their tumor-promoting roles are unclear.

Methods: Targeted sequencing was employed to evaluate a core panel of genes implicated in histone methylation (EZH2, KMT2D), histone acetylation (CREBBP, EP300), and chromatin remodeling (ARID1A, BCL7A) in FL patients. Functional characterization of the KMT2D mutation (KMT2D^mut) was carried out in vitro. RNA sequencing analysis was utilized to identify differentially expressed genes (DEGs) and significantly enriched pathways. The role of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) in mediating the function of the KMT2D^mut was investigated in B-lymphoma cell models using lentivirus. Through transcriptome deconvolution, integrative analyses combining chromatin immunoprecipitation and genome-wide chromatin accessibility were performed in KMT2D-mutant cell lines. Additionally, chromatin immunoprecipitation, immunofluorescence assays, and immunoblotting analyses were conducted.

Results: KMT2D mutations were the most frequent genetic alterations in FL (63%), predominantly consisting of nonsense and frameshift variants. Compared with wild-type, KMT2D-mutant FL exhibited markedly reduced H3K9me3 levels and increased chromatin accessibility at distal regulatory regions. Functionally, KMT2D^mut promoted proliferation, suppressed apoptosis, and arrested cells in G2 phase. In FL, mutant KMT2D suppressed H3K9 methylation, leading to ALDH1A1 upregulation and the emergence of a highly plastic B‑cell state, followed by ATP7A overexpression, which ultimately reshaped the immune microenvironment.

Conclusions: KMT2D^mut drives FL progression by relieving H3K9me3-mediated epigenetic modification, activating PDK1/SGK1 signaling and an ALDH1A1-driven stemness program, and upregulating ATP7A to rewire copper homeostasis and redox balance. Our findings delineate a central molecular network through which KMT2D^mut operates in FL and provide a mechanistic rationale for therapeutic targeting of KMT2D.