Document jBBgep7Bw5BokkZLn5JnQV2rR

ELSEVIER Available online at www.sciencedirect.com '0*;# #'ij,,'N // ScienceDirect Leukemia Research xxx (2007) xxx-xxx Leukemla Research www.elsevier.com!1ocate!1eukres The TNF-a 238A polymorphism is associated with susceptibility to persistent bone marrow dysplasia following chronic exposure to benzene Ling Lvil,e, Patrick Kerzica,c, Guowei Line, A. Robert Schnatter g, Liming Baoa,f, Yongchen Yangil, Hejian Zou e, Hua Fu b, Xibao Ye b, Sherilyn A. Grossil,c, Thomas W. Armstrong g, Richard D. Ironsa,c,d,* a International Clinical and Molecular Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China b School ofPublic Health, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China C Department ofPharmaceutical Sciences, School ofPharmacy, 4200 E. 9th Avenue/Box C238, University of Colorado at Denver and Health Sciences Center, Denver, CO 20262, USA d Department ofPathology, School ofMedicine, AlP Bldg'/Box F768, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA e Huashan Hospital, Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China f Division ofHuman Genetics, University of Cincinnati Children's Hospital Medical Center, 3333 BurnettAvenue, Cincinnati, OH 45229-3039, USA g ExxonMobil Biomedical Sciences Inc., 1545 Route 22 East, Annandale, NJ 08801-0971, USA Received 3 November 2006; received in revised form 16 January 2007; accepted 18 January 2007 Abstract Chronic exposure to benzene can result in transient hematotoxicity (benzene poisoning, BP) or persistent bone matTOW pathology including dysplasia and/or acute myeloid leukemia. We recently described a persistent bone matTOW dysplasia with unique dysplastic and inflammatory features developing in individuals previously exposed to benzene (BID) [Irons RD, Lv L, Gross SA, Ye X, Bao L, Wang XQ, et aL Chronic exposure to benzene results in a unique fmID of dysplasia. Leuk Res 2005;29:1371-80]. In this study we investigated the association of single nucleotide polymorphisms (SNP) (-863 (C --+ A), -857 (C --+ T), -308 (G --+A), -238 (G --+ A in the promoter region of the cytokine, tumor necrosis factor-alpha (TNF-O') on the development of BP, persistent BID and de novo myelodysplastic syndrome (MDS) in 394 individuals. Only the -238 (G --+ A) polymorphism was significantly associated with the development of BID (odds ratio (OR) = 7.4; 95% C.L 1.23-44.7) and was specific for BID and not de novo MDS or BE These findings are consistent with a role for inflatnmation in the development of BID and suggest that cell-specific alterations in TNF-O' expression may promote clonal selection in the evolution of neoplastic hematopoietic disease. 2007 Elsevier Ltd. All rights reserved. Keywords: Benzene poisoning; 1NF-O' promoter gene polymorphisms; Leukemogenesis; Clonal selection; Genetic variation; Inflammation; Epidemiology; Toxins/dmgs/xenobiotics * Corresponding author at: University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Avenue/Box C238 Denver, CO 80262, United States. TeL: +1 303 3157170; fax: +1303 3157237. E-mail address: richard.irons@uchsc.edu (RD. Irons). 0145-2126/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi: 10.1016ij Jeukres.2007 .01.014 1. Introduction Benzene is a widely known hematotoxic agent. However, the severity of hematotoxicity associated with chronic exposure to benzene varies widely. Individuals undergoing comparable exposure may demonstrate no significant hematologic abnormalities while others exhibit signs of benzene poisoning (BP) or even bone marrow failure. Some individ- SH ELL-MCCLU RG-059256