Abstract
Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL) showed differential expression of Ran GTPase-activating protein 1 (RanGAP1) between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50) were RanGAP1+, while reactive lymphoid hyperplasia (n = 12) was RanGAP1+ predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180) with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95%) or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin’s lymphoma 91%). Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62) than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52) and healthy controls (0.55 ± 1.58 ng/mL, n = 75) (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test). In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035) and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030) along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon), a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.
Highlights
Tumor biomarkers are pivotal for screening, diagnosing, and following-up cancers
Proteomic analysis yielded 20 proteins overexpressed in Diffuse large Bcell lymphoma (DLBCL) cell lines compared with the Blymphoblastoid cell line
Two DLBCL cell lines (HT and SU-DHL-5) and a Blymphoblastoid cell line (LCL) were used for comparison to search for candidate biomarkers from cell lysates
Summary
Tumor biomarkers are pivotal for screening, diagnosing, and following-up cancers. Current clinically useful biomarkers for lymphoma management are both scarce and non-specific. Serum lactate dehydrogenase (LDH) is a widely used biomarker in lymphoma patients and is linked to prognosis [1]. Its low specificity limits its clinical application because, in addition to tumor progression, an elevated LDH level is found in other non-neoplastic conditions, such as myocardial damage [2]. LDH provides no insight into tumor biology [3]. Serum beta-2 microglobulin, an established prognostic factor for multiple myeloma, has been used for non-Hodgkin’s lymphoma patients as a prognostic factor [4]. Its low specificity and sometimes low sensitivity diminish its clinical utility [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
