Venetoclax

B-cell lymphoma 2 (BCL-2) is an important anti-apoptotic protein in the mitochondrial cell death pathway and is biologically significant for leukemic cell survival, apoptosis resistance, drug resistance, and disease persistence. BCL-2 is clinically relevant in hematopathology and laboratory medicine, as it is a central regulator of apoptosis in several leukemia subtypes. This review evaluates BCL-2 primarily as a prognostic, treatment-stratifying, and venetoclax-related predictive biomarker in leukemia, while critically examining its more limited and context-dependent diagnostic contribution. We summarize existing data on the association of BCL-2 expression and functional dependency with leukemia biology, cytogenetic and molecular risk factors and survival. We also explore its use in distinguishing leukemic populations from non-malignant hematopoietic populations, primarily in conjunction with morphology, immunophenotyping, cytogenetics, molecular testing, and other markers of apoptosis. Laboratory considerations for clinical implementation are addressed, such as specimen selection, inter-platform variability, antibody and gating strategies, immunohistochemistry, flow cytometry, transcript-based assessment, functional apoptotic profiling, and preanalytical, analytical, and interpretative variability. We also discuss the clinical relevance of BCL-2 in venetoclax-based therapy, where dependence on BCL-2 may be more informative than expression. Overall, BCL-2 is better supported as prognostic and treatment-stratifying marker than a diagnostic marker in leukemia. To move BCL-2 assessment into routine laboratory practice, it will be necessary to establish harmonized thresholds for BCL-2 assays and to validate the analytical workflow and result in prospective studies. This review outlines the potential and current challenges of BCL-2 as an emerging biomarker in human leukemia within a laboratory medicine framework.