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Blood, 1 January 2007, Vol. 109, No. 1, pp. 290-297.
Prepublished online as a Blood First Edition Paper on September 7, 2006; DOI 10.1182/blood-2006-03-007567.
 Previous Article | Next Article 
Submitted March 6, 2006
Accepted August 16, 2006
Association of a novel regulatory polymorphism (-938C>A)
in the BCL2 gene promoter with disease progression and
survival in chronic lymphocytic leukemia
Holger Nuckel*, Ulrich H Frey, Maja Bau, Ludger Sellmann, Jens Stanelle, Jan Durig, Karl-Heinz Jockel, Ulrich Duhrsen, and Winfried Siffert
Dept. of Hematology, Institute of Pharmaco. Medical Faculty, University of Duisburg-Essen, Germany
Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Germany
Institute of Pharmacogenetics
Dept. of Hematology, Institute of Cell Bio, Medical Faculty, University of Duisburg-Essen, Germany
Institute of Cell Biology (Tumor research), University of Duisburg-Essen, Germany
Department of Hematology, Medical Faculty, University of Duisburg-Essen, Germany
Institute for Medical Informatics, Biometry and Epidemiology
Institute for Medical Informatics, Medical Faculty, University of Duisburg-Essen, Germany
* Corresponding author; email: holger.nueckel{at}uni-essen.de.
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-CLL. The -938C-allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared to the A-allele. Concomitantly, Bcl-2 protein expression in B-cells from CLL patients carrying the -938 AA genotype was significantly increased compared to 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 to AC/CC genotypes (120 and 321 months, respectively; p=0.0077 and p=0.003, 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=0.034) together with disease stage at diagnosis (HR 2.5; p=0.004) and ZAP-70 status (HR 3.0; p=0.001).
The BCL2 -938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.
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