The elusive predisposing polymorphism: MDR1 and lymphoma

The human genome is highly polymorphic [1]. While variations in regions encoding protein are relatively rare and may cause disease, most of the genome does not code for proteins and therefore is highly variable. It is estimated that up to 1 in 10³ nucleotides may be polymorphic [1]. Single nucleotide polymorphisms (SNPs) in coding or non-coding regions of a multitude of genes have been studied for their role in causing diseases or for underlying variations in response to therapy. One gene studied intensively for these effects is the multidrug resistance gene, MDR1 (ABCB1). This gene, identified in 1985, spans over 200 kb, and comprises 28 exons. Polymorphisms were found to be numerous: by 2003, nearly 50 polymorphic sites were described [2]. In this issue of Leukemia and Lymphoma, Hu et al. [3] explore the impact of several SNPs in MDR1 regarding the predisposition to, and response to treatment of, diffuse large B cell non-Hodgkin lymphoma (NHL) in Chinese Hans. Three of the polymorphisms studied by this group have been widely studied elsewhere in other diseases such as acute myeloid leukemia; these are C1236T, G2677T(A) and C3435T. The T allele at both 2677 and 3435 SNPs were found here to adversely affect the outcome of diffuse large B cell lymphoma (DLBCL), which is in agreement with similar studies of other malignancies, both hematological and solid tumors. The G2677T encodes an amino acid change in exon 21 (Ala to Ser) and has been suggested by a number of studies, including this one, to have a negative prognostic effect. The C3435T SNP in exon 26 is more complex as it is synonymous (that is, it does not encode an amino acid change). Therefore its effect on gene expression is harder to explain. A pivotal study [4] demonstrated a biological change in transporter function depending on the DNA sequence. This group implied that codon usage affects translation, leading to differences in protein folding and tertiary structure, causing a change in activity despite the lack of alteration in amino acid sequence [4].

The influence of SNPs in promoter regions on gene expression is not always easily understood. Pioneering studies in the 1980s on the β- and γ-globin genes of hemoglobin revealed much about invariant promoter elements required for correct gene function. The functional importance of the MDR1 promoter region is suggested by the fact that its sequence is largely invariant [5]. However, a few SNPs are found in the MDR1 promoter in locations which are not known to be necessary for proper transcription or translation. One such SNP is MDR1 C-129T, which was first reported in 1999 [6] (then referred to as being located + 8 to the transcription start site and later renamed for its location relative to the site of translation initiation). Subsequently, several studies have demonstrated DNA binding by nuclear proteins in certain MDR1 promoter regions. For instance, at the − 129 site, nuclear extracts from colon cells demonstrate a DNA–protein interaction [7], suggesting a functional role for this region.

Whether a polymorphism influences development of a disease depends on at least two factors: (a) whether the polymorphism affects gene expression (or is linked to another element affecting expression); (b) whether or not the specific gene is involved in the pathogenesis of the particular disease, considering the tissue specific expression of the gene. Thus, a question that arises from the study of Hu et al. [3] is: how does the SNP at − 129 predispose to developing DLBCL? This is a unique observation from this study, which has not been noted previously. Lymphoid cells indeed express MDR1, with B cells expressing MDR1 at lower levels than T cells but higher than neutrophils and monocytes, as measured by RNA analysis and rhodamine 123 efflux [8]. This may suggest a role for MDR1 in lymphomagenesis in relation to the efflux of toxins, such as pesticides or solvents, which have been linked by epidemiology to NHL [9]. However, a newly described function of MDR1 may be related to a role in lymphomagenesis, which is separate from its role as a transporter: MDR1 has recently been shown to have a role as a regulator of apoptosis, via regulation of miRNA (miR-16) and BCL2 [10]. Several recent reports have pointed to a role of MDR1 in apoptosis in various cell types (kidney tubules, breast and gastric cancer, etc.). In lymphoid cells, in vitro studies have shown that MDR1 overexpression in a human lymphoblastoid cell line resulted in up-regulation of apoptosis related genes and reduced apoptosis in response to radiation [11]. These findings certainly enable formulating a reasonable hypothesis for a relationship between MDR1 and lymphomagenesis, considering current evidence on the multifactorial pathogenesis of lymphoma [12]. Future studies will hopefully clarify the precise mechanism of these interactions. In the mean time, comprehension of the relationship between C-129T and DLBCL remains elusive.

Potential conflict of interest

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