Discovery of BEND4 as a novel single-gene prognostic marker and therapeutic target for adverse AML.
Source: PubMed, NCBI / U.S. National Library of Medicine
Acute myeloid leukemia (AML) presents significant clinical challenges due to patient heterogeneity and variable treatment responses. Cytogenetic and mutation-based biomarkers dominate current prognostic classifications. However, many patients lack these canonical markers, and most are not therapeutic targets. Gene expression-based biomarkers, despite their clinical potential, remain underexplored. Here, we used transcriptome analyses of primary AML cohorts (n = 1338) and identified BEN domain-containing protein 4 (BEND4) as significantly overexpressed in adverse cytogenetic risk. Independent validation (n = 350) showed BEND4 was significantly overexpressed in relapse and refractory AML patients. High BEND4 expression was associated with poor overall survival, increased relapse risk, and was an independent risk factor in AML. Furthermore, in prognostic prediction, BEND4 expression outperformed mutation or gene expression-based models and a Δct threshold from RT-qPCR of <12.75 differentiated adverse risk AML patients with 91% sensitivity and 81% specificity. Functionally, BEND4 perturbation modulated chemoresistance to doxorubicin and cytarabine, apoptosis, cell cycle distribution, cellular proliferation and clonogenicity, by altering several oncogenic and inflammation-related molecular pathways. In vivo, BEND4 overexpression promoted leukemogenesis and shortened survival, whereas its suppression decreased tumor burden and improved survival. Th
Abstract
Acute myeloid leukemia (AML) presents significant clinical challenges due to patient heterogeneity and variable treatment responses. Cytogenetic and mutation-based biomarkers dominate current prognostic classifications. However, many patients lack these canonical markers, and most are not therapeutic targets. Gene expression-based biomarkers, despite their clinical potential, remain underexplored. Here, we used transcriptome analyses of primary AML cohorts (n = 1338) and identified BEN domain-containing protein 4 (BEND4) as significantly overexpressed in adverse cytogenetic risk. Independent validation (n = 350) showed BEND4 was significantly overexpressed in relapse and refractory AML patients. High BEND4 expression was associated with poor overall survival, increased relapse risk, and was an independent risk factor in AML. Furthermore, in prognostic prediction, BEND4 expression outperformed mutation or gene expression-based models and a Δct threshold from RT-qPCR of <12.75 differentiated adverse risk AML patients with 91% sensitivity and 81% specificity. Functionally, BEND4 perturbation modulated chemoresistance to doxorubicin and cytarabine, apoptosis, cell cycle distribution, cellular proliferation and clonogenicity, by altering several oncogenic and inflammation-related molecular pathways. In vivo, BEND4 overexpression promoted leukemogenesis and shortened survival, whereas its suppression decreased tumor burden and improved survival. This study establishes BEND4 as a clinically relevant single gene expression-based biomarker and a potential therapeutic target in AML.