High levels of topoisomerase IIα protein expression in diffuse large B-cell lymphoma are associated with high proliferation, germinal center immunophenotype, and response to treatment

Abstract

Gene copy number and protein expression of topoisomerase IIalpha were correlated to benefit from anthracyclines in various tumors. A retrospective series of 69 patients with DLBCL managed with CHOP chemotherapy were studied for immunohistochemical TopoIIalpha expression and numerical gene abnormalities by fluorescent in situ hybridization (FISH). The results were analyzed in relation to the expression of cell cycle proteins (Ki67, p53, HDM2, p21, p14, pRb, p16, and cyclins A, B1, D1, D2, D3, and E) and BCL6/CD10/MUM1/CD138 B-cell differentiation immunophenotype and outcome. High levels of TopoIIalpha protein were found in 91% of DLBCL cases. No evidence of TopoIIalpha gene amplification or deletion was found. The TopoIIalpha expression showed significant positive correlations with the proliferation index Ki67 (p = 0.002), cell cycle proteins pRb and cyclin D2 (p = 0.018 and p = 0.028, respectively), and the germinal center proteins bcl6 and CD10 (p = 0.010 and p < 0.0001, respectively). TopoIIalpha expression was significantly higher in germinal center B-cell like (GCB) DLBCL than in non-germinal center B-cell like (non-GCB) DLBCL (p = 0.048). TopoIIalpha protein was significantly associated with response to chemotherapy (chi(2), p = 0.024), but not with relapse-free or overall survival (p = 0.5). On multivariate analysis, only stage of disease retained independent prognostic significance (HR 0.33 for early stage, p = 0.008). Although TopoIIa gene copy number abnormalities were not found in DLBCL, high levels of protein expression are associated with GCB-cell differentiation immunophenotype, high proliferation, and response to treatment.

Cancer Resistance to Type II Topoisomerase Inhibitors

“…Despite the wealth of studies in this field, none of the proposed mechanisms of resistance to TOPO2 inhibitors is currently considered reliable enough to be exploited on the clinical ground. In fact, although several reports have supported the use of TOPO2 expression levels to select patients more likely to respond to TOPO2 inhibitors [66][67][68][69], a very recent meta-analysis appears to temper the enthusiasms and overall discourages from using this approach for treatment personalization [70]. In addition, no efflux pump inhibitor is currently considered a standard companion of TOPO2 poisons in any chemotherapy regimen.…”

Aberrant activation of ubiquitin D at G₂ phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

“…Overexpression of Topo IIα indicates a high level of proliferation in neoplastic cells (Pentheroudakis et al, 2010). We have previously demonstrated that an increase in Topo IIα + cells indicates cell proliferation following treatment with renal carcinogens (Taniai et al, 2012).…”

Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

“…QAP1 (quinoline aminopurine 1) is an ATP-competitive hTopoII inhibitor which is shown to target both TopoIIα and β isoforms [26]. TopoIIα has been thought to be the main target of topoisomerase poisons like etoposide and doxorubicin, however there is also evidence suggesting that etoposide induced DNA sequence rearrangements and double strand breaks are TopoIIβ dependent [27,28]. NK314, a topoisomerase II poison has been described to be TopoIIα specific agent with in vitro activity against non-small cell cancer, colorectal cancer and human cervical cancer cells [29].…”