Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia.
Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The -938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the -938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with -938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2-938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2-938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.
Nückel
Holger
H
Department of Hematology, Medical Faculty, University of Duisburg-Essen, Germany. holger.nueckel@uni-essen.de
Frey
Ulrich H
UH
Bau
Maja
M
Sellmann
Ludger
L
Stanelle
Jens
J
Dürig
Jan
J
Jöckel
Karl-Heinz
KH
Dührsen
Ulrich
U
Siffert
Winfried
W
D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002460:Cell Line; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure; D018450:Disease Progression; D005260:Female; D019254:Genes, bcl-2; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D014158:Transcription, Genetic; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human