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. Overall design: This study employed an integrated experimental framework combining bioinformatics, in vitro functional assays, and in vivo validation. Public transcriptomic datasets (TCGA-LAML, GTEx, GEO) were analyzed to evaluate BCL6B and GGT5 expression patterns, clinical associations, and prognostic relevance. Clinical bone marrow samples from AML patients and healthy donors were used for expression validation by RT-qPCR. Gain- and loss-of-function experiments were performed in multiple AML cell lines using lentiviral-mediated BCL6B overexpression or shRNA knockdown. Cell proliferation, apoptosis, and cell cycle distribution were assessed by CCK-8 assays and flow cytometry. Epigenetic regulation of BCL6B was examined using methylation-specific PCR and decitabine treatment. RNA sequencing was conducted to identify BCL6B-regulated genes, followed by GO and KEGG pathway enrichment analyses. Direct transcriptional regulation of GGT5 by BCL6B was validated using dual-luciferase reporter assays and electrophoretic mobility shift assays. MAPK pathway activation was analyzed by Western blotting. Functional rescue experiments were performed by co-overexpression of GGT5 and BCL6B. In vivo effects were evaluated using zebrafish and nude mouse xenograft models to assess tumor growth, migration, angiogenesis, and survival.