Thymidylate Synthase (TS) Expression In Diffuse Large B-Cell Lymphoma (DLBCL): Identification of a Potential Therapeutic Target

TS is critical for the de novo synthesis of thymidine needed for tumor cell proliferation and DNA damage repair, whereas thymidine kinase 1 (TK1) is key to the salvage pathway providing thymidine recovered from plasma. While TK1 expression has been previously shown to correlate with proliferation in DLBCL, little is known about TS levels in these neoplasms. We hypothesized that, similarly to TK1, TS expression levels associate with increased proliferation and thus may represent a novel therapeutic target in large cell lymphoma.

To address this hypothesis, we determined the expression of TS in lymph node biopsies from 43 DLBCL patients sequentially enrolled in the study with no pre-selection criteria other than the primary histological diagnosis of lymphoma, and then compared it to TK1 expression. In addition, Ki-67 (MIB1) was included as an established marker of cell proliferation. Pearson correlation along with the correlation coefficient and two-tailed P values were calculated to measure the extent of covariation.

TS expression and both MIB1 and TK1 were significantly correlated with correlation coefficients of 0.43 and 0.65, respectively (95% CI 0.13 to 0.65 and 0.44 to 0.8; P values = 0.006 and <0.0001, respectively). The correlation between TS and MIB1 expression was in fact stronger than between MIB1 and TK1 (P values 0.006 and 0.04, respectively). Mean percent positive cells and standard deviations for MIB1, TS and TK1 were 44.5% (SD=35), 51.8% (SD=33.4), and 44% (SD=28.5), respectively. Despite the general good correlation, however, six patients had relatively high TS levels (defined as % cell staining above the mean for TS) and relatively low TK1 levels (% cell staining below the mean for TK1), while the reverse was true in seven patients. Eight patients had high levels of TK1 and TS with ≥ 70% cells positive for both; seven patients had low levels of both proteins (≤30% of cells stained).

This is the first report of TS expression in DLBCL. TS is frequently expressed in DLBCL and there is a significant correlation between TS and TK1 or MIB1 expression. Further studies are warranted to determine the correlation between TS or TK1 expression and patient prognosis in comparison to MIB1. Importantly, the common expression of TS in patients with DLBCL indicates that TS may be a suitable target for TS inhibitors (TSIs) in these neoplasms. Preclinical studies are underway to test this hypothesis.

No relevant conflicts of interest to declare.