Data from <i>Bim</i> Polymorphisms: Influence on Function and Response to Treatment in Children with Acute Lymphoblastic Leukemia

Abstract

<div>Abstract<p><b>Purpose:</b> Corticosteroids induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies showed major implication of proapoptotic <i>Bim</i> in mediating corticosteroid-related resistance in leukemia cells.</p><p><b>Experimental Design:</b> We investigated <i>Bim</i> gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding.</p><p><b>Results:</b> Lower overall survival (OS) was associated with <i>Bim</i><i>C29201T</i> located in <i>Bcl-2</i> homology 3 (BH3) domain (<i>P</i> = 0.01). An association remained significant in multivariate model (<i>P</i> = 0.007), was more apparent in high-risk patients (<i>P</i> = 0.004) and patients treated with dexamethasone (<i>P</i> = 0.009), and was subsequently confirmed in the replication patient cohort (<i>P</i> = 0.03). RNA analysis revealed that <i>C29201T</i> affects generation of γ isoforms (γ1) that lack proapoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with <i>Bim</i> genotype. Combined analysis with <i>Mcl</i> gene polymorphism (<i>G-486T</i>) revealed profound reduction in OS in individuals with both risk genotypes (<i>P</i> < 0.0005 in discovery and <i>P</i> = 0.002 in replication cohort) and particularly in high-risk patients (<i>P</i> ≤ 0.008).</p><p><b>Conclusions:</b> Increased expression of prosurvival <i>Mcl1</i> and presence of <i>Bim</i> isoforms lacking proapoptotic function might explain marked reduction of OS in a disease and dose-dependent manner in ALL patients carrying <i>Bim</i>- and <i>Mcl1</i>-risk genotypes. <i>Clin Cancer Res; 19(18); 5240–9. ©2013 AACR</i>.</p></div>