Research Article: Discovery and validation of a robust 11-gene prognostic signature via integrative multi-omics profiling in VD-CAG-treated non-M3 AML
Abstract:
While the venetoclax-based VD-CAG regimen has shown promising efficacy in acute myeloid leukemia (AML), its underlying molecular response mechanisms remain poorly understood, and robust prognostic biomarkers for non-M3 AML treated with this regimen are lacking. This study aimed to elucidate the molecular alterations associated with VD-CAG treatment response, and to identify and validate robust prognostic biomarkers to improve risk stratification for non-M3 AML patients.
This study enrolled 15 non-M3 AML patients receiving VD-CAG induction therapy, and conducted integrative multi-omics profiling of their bone marrow samples: RNA sequencing was performed on 10 pairs of pre- and post-treatment samples, while data-independent acquisition (DIA) proteomics was applied to another 5 paired samples. Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules correlated with composite complete remission. A prognostic signature was further derived using Least Absolute Shrinkage and Selection Operator (LASSO) regression, with the TCGA-LAML cohort as the discovery set and the independent Beat AML cohort as the external validation set.
Transcriptomic analysis revealed that differentially expressed genes after VD-CAG treatment were mainly enriched in MAPK signaling and cell adhesion pathways. WGCNA identified five gene modules significantly correlated with treatment remission. We finally constructed a robust 11-gene prognostic signature ( TLN1, ARL15, PDZD2, ACER2, IGF2BP3, TMEM200A, DOCK1, SYTL4, CPNE8, FNDC3B , and MANBA ), which effectively stratified patients' overall survival. This signature showed strong predictive performance in both the discovery cohort (TCGA: HR=3.60, p =7.6e-10; 3-year AUC=0.79) and the independent validation cohort (Beat AML: HR=1.89, p =1.3e-3; 3-year AUC=0.83). Proteomic analysis identified 447 differentially expressed proteins between pre- and post-treatment samples, among which FNDC3B, a key protein in the prognostic signature, was significantly downregulated after VD-CAG intervention.
This study reveals the molecular alterations associated with VD-CAG treatment in non-M3 AML, and provides a validated 11-gene prognostic signature. These findings enhance our understanding of the response mechanisms of the VD-CAG regimen, and offer a tool to improve prognostic stratification and clinical decision-making for non-M3 AML patients.
Introduction:
Acute myeloid leukemia (AML) remains the most common acute leukemia in adults, characterized by the uncontrolled proliferation of immature myeloid blasts in the bone marrow and peripheral blood, leading to bone marrow failure and life-threatening complications ( 1 ). In contrast to acute promyelocytic leukemia (APL or M3), non-M3 AML represents the majority of cases and presents unique treatment challenges, such as higher relapse risks and the need for intensive chemotherapy ( 2 ). Despite advances in therapeutic…
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