The Dual Role Of Myc And Bcl-2 Overexpression In Leukemia Progression, Drug Resistance, And Therapy

Abstract

Leukemia treatment is frequently challenged by drug resistance, particularly in cases involving dysregulated survival pathways such as MYC and BCL-2 overexpression. This study aimed to investigate how MYC and BCL-2 contribute to both intrinsic and acquired resistance to chemotherapy and targeted therapies in leukemia cells. Using gene-modified leukemia cell lines, we demonstrated that MYC overexpression led to a 3.5-fold and 2.8-fold increase in resistance to cytarabine and daunorubicin, respectively. BCL-2 overexpression significantly increased resistance to venetoclax, with the IC₅₀ rising from 12 nM to 51 nM (4.2-fold). Furthermore, MYC-overexpressing cells remained resistant to JQ1, a BET inhibitor, with a 2.5-fold higher IC₅₀, suggesting alternative resistance mechanisms independent of BCL-2. To model acquired resistance, cells were exposed to increasing concentrations of venetoclax or JQ1 over several weeks. Venetoclax-resistant cells showed a 3.9-fold increase in IC₅₀ and a 2.8-fold upregulation of MCL-1, indicating a survival shift from BCL-2 to MCL-1. JQ1-resistant cells demonstrated a 3.6-fold increase in ABCB1 (P-glycoprotein) expression, promoting active drug efflux. Apoptosis assays confirmed resistance at the functional level, showing a 60% reduction in Cleaved Caspase-3 in venetoclax-resistant cells and a 53% decrease in apoptosis induction in JQ1-resistant cells. Additionally, transcriptomic profiling revealed upregulation of survival genes such as BCL2A1 and BIRC5. These findings highlight the complex and multifactorial nature of drug resistance in leukemia, driven by both apoptotic evasion and drug efflux. Targeting these adaptive resistance mechanisms may enhance therapeutic efficacy and help overcome treatment failure in leukemia.