Apoptosis gene expression analysis identifies biologically distinct AML clusters and BIK as an independent prognostic...

Dysregulation of apoptosis is a key feature of acute myeloid leukemia (AML) and contributes to therapy resistance, yet the clinical relevance of apoptosis-related gene expression remains incompletely understood. We prospectively analyzed mRNA expression of apoptosis-related genes in bone marrow mononuclear cells from 90 newly diagnosed AML patients. Gene expression clustering identified two biologically distinct patient groups. The subgroup with significantly inferior overall survival (Cluster 2) showed coordinated upregulation of pro-apoptotic genes, including BCL2L11 (BIM), BBC3 (PUMA), BID, BAD, BIK, and BAX, together with a shift in anti-apoptotic signaling toward lower BCL2 expression and increased expression of alternative survival regulators, MCL1 and BCL2L1 (BCL-xL). Reduced expression of executioner caspases CASP3 and CASP7 was also observed in Cluster 2, which may indicate less efficient apoptotic execution. Among patients treated with venetoclax + azacitidine (VenAza), Cluster 2 demonstrated significantly shorter event-free survival. This finding is consistent with the biological features of Cluster 2, including a monocytic immunophenotype previously associated with reduced sensitivity to BCL-2-targeted therapy and increased reliance on alternative anti-apoptotic regulators such as MCL1 and BCL-xL. Analysis of individual genes showed that higher BIK mRNA expression was associated with poorer survival and lack of response to VenAza, highlighting the paradoxical association between increased expression of this pro-apoptotic gene and adverse clinical outcome. These findings demonstrate that dysregulation of apoptosis-related gene expression defines clinically distinct AML subgroups and may contribute to differences in prognosis and therapeutic response.