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

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 (KMT2Dmut) 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 KMT2Dmut 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, KMT2Dmut 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

KMT2Dmut 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 KMT2Dmut operates in FL and provide a mechanistic rationale for therapeutic targeting of KMT2D.