ASSOCIATION OF –308TNF AND +252LTA SINGLE NUCLEOTIDE POLYMORPHISMS WITH HEMATOLOGICAL MALIGNANCIES IN CHILDREN FROM THE BASHKORTOSTAN REPUBLIC
Yakupova EV 1,* Krasavtceva TN2, Malyevsky OA2, Viktorova TV1
*Corresponding Author: Dr. Elvira V. Yakupova, Institute of Biochemistry and Genetics, Ufa Research Centre, Russian Academy of Science, Prospect Oktyabrya 69, Ufa 450054, Russia; Tel./Fax: +007-3472-356088; E-mail: ecolab_203@mail.ru
page: 9

DISCUSSION

A polymorphism, that directly affected the TNF gene expression in vitro, was located at nucleotide position –308GŪA [14,15]. The presence of the TNF*G allele defined a 10 bp sequence homologous to the activator protein –2 (AP-2) binding site, that is disrupted in the TNF*A variant. Functional assays demonstrated that AP-2 could repress the promoter of the TNF gene in the Jurkat T-cell line, suggesting that the –308 polymorphism influ­enced the TNF gene expression. Transfection studies in the human B-cell line showed that the presence of the TNF*A allele results in higher constitutive and inducible levels of TNF expression when compared with the TNF*G allele, confirming the importance of this site in the transcriptional regulation of the TNF gene [14,15].


A polymorphism, that affected LTA expression, was found in the first intron of the gene at nucleotide position +252AŪG [8]. This polymorphism was located within a phorbol-ester-responsive DNA element with a high affinity to the activator proteins (AP-1, JUN) and c-fos hetero­dimer transcription factor family. The presence of the LTA*GG genotype was shown to result in a significantly higher production of LTA by phytohemagglutinin-stimu­lated peripheral blood mononuclear cells due to an in­crease of LTA gene transcription [8].

Several studies have demonstrated the linkage dis­equilibrium between both –308TNF and +252LTA poly­morphic sites, and with other allelic markers within the cluster of HLA genes [6]. In the present study, we assumed that these polymorphisms were in association with differ­ent forms of hematological malignancies in children.

We have not found any statistically reliable associa­tion between –308TNF and +252LTA polymorphisms and ALL. Our results did not contradict those of Stanulla et al. [16] who did not find any association between –308TNF and +252LTA gene polymorphisms and children with ALL. Takeuchi et al. [17] also proved that genetic poly­morphisms in the TNF locus had a limited effect on the outcome of childhood ALL.

TNF*GA and LTA*AG genotypes in our study were associated with AML in children. Probably, higher consti­tutive and inducible transcription level of the TNF and LTA genes had an impact on the poor outcome of the most aggressive form of hematological malignancies in chil­dren.

The TNF*GG and LTA*AA genotypes proved to be associated with NHL. We can assume that low constitutive and inducible transcription levels of the TNF and LTA genes play a protective role in the development and out­come of this disease. This theory did not contradict the results of Warzocha et al. [12], who indicated that genetic polymorphisms leading to increased TNF production were associated with the poor outcome of NHL. We think that additional investigations, including patients of all clini­cally



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