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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319662 | GEO | 2026/03/01

REPOSITORIES: GEO

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Project description:To evaluate if p53 decreases Kruppel-Like Factor 2 (KLF2) expression and determine whether p53-mediated suppression of KLF2 plays a role in p53-induced endothelial dysfunction.Endothelial KLF2 mediates endothelium-dependent vascular homeostasis by differentially regulating endothelial genes, leading to an anti-inflammatory and antithrombotic endothelial surface with normal vasodilatory function. In contrast, the tumor suppressor p53 leads to inflammatory gene expression and impairs endothelium-dependent vasodilatation, thus promoting endothelial dysfunction. The effect of p53 on KLF2 expression was determined. p53 inhibited KLF2 transcription in a histone deacetylase-dependent and a histone acetyltransferase-independent fashion. KLF2 expression was suppressed by p53 via a conserved p53-binding repressor sequence in its promoter. p53 bound to, and stimulated, deacetylation of Histone H3 at the KLF2 promoter. The effect of p53 on endothelial KLF2 target genes was examined. Downregulation of p53 increased expression of endothelial NO synthase and thrombomodulin and inhibited expression of plasminogen activator inhibitor 1. Conversely, overexpression of p53 suppressed endothelial NO synthase and thrombomodulin expression and stimulated plasminogen activator inhibitor 1 and endothelin-1 expression. Knockdown of KLF2 abolished the p53-induced decrease in thrombomodulin and increase in endothelin-1. Both, overexpression of p53 and knockdown of KLF2 in endothelial cells increased blood coagulation on an endothelial cell monolayer. The p53-induced increase in coagulation was rescued by forced expression of KLF2. p53 also impaired endothelium-dependent vasodilatation and decreased bioavailable vascular NO, both of which were rescued by forced KLF2 expression.These findings illustrate a novel p53-dependent mechanism for the regulation of endothelial KLF2 expression. In addition, they show that downregulation of KLF2, in part, mediates a p53-stimulated dysfunctional endothelium.

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

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