BCL6B suppresses acute myeloid leukemia progression by transcriptionally repressing GGT5 and modulating MAPK signaling

Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy with poor prognosis. In this study, we investigated the role of B-cell lymphoma 6 member B (BCL6B) in AML progression. Integrated analyses of TCGA-LAML, GTEx, and GEO datasets revealed that BCL6B was significantly downregulated in AML and associated with adverse clinical features and shorter overall survival. Functional assays demonstrated that BCL6B overexpression suppressed AML cell proliferation, induced apoptosis, and caused G0/G1 cell cycle arrest, whereas BCL6B knockdown exerted opposite effects. Mechanistically, transcriptome analysis and promoter-binding assays identified gamma-glutamyltransferase 5 (GGT5) as a direct transcriptional target of BCL6B. BCL6B bound to the GGT5 promoter and repressed its expression, thereby modulating MAPK signaling by inhibiting ERK phosphorylation and activating p38 and JNK pathways. Rescue experiments confirmed that GGT5 partially mediated the biological effects of BCL6B. In vivo, BCL6B overexpression significantly inhibited leukemic growth, migration, angiogenesis, and improved survival in zebrafish and mouse xenograft models. These findings identify the BCL6B–GGT5–MAPK axis as a key regulatory pathway in AML and a potential therapeutic target.