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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.
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NEOPLASIA
Association of a novel regulatory polymorphism (–938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia
Holger Nückel1,2,,
Ulrich H. Frey2,
Maja Bau2,
Ludger Sellmann1,4,
Jens Stanelle4,
Jan Dürig1,
Karl-Heinz Jöckel3,
Ulrich Dührsen1, and
Winfried Siffert2
1 Department of Hematology and
2 Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Germany;
4 Institute of Cell Biology (Tumor research), University of Duisburg-Essen, Germany; and
3 Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, Germany
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.
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