DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

Abstract

DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia

“…The protein is frequently expressed in diffuse large B-cell lymphoma (DLBCL) being highly associated with Ki-67 expression as demonstrated in our multi-centre series of DLBCL cases. 41 We also showed that stable knockdown of DNMT1 in DLBCL cells upregulated expression of genes involved in the activation of cell cycles, 42 similar with the DNMT1- p15 axis (p15 protein inhibits cell cycle progression) frequently reported in AML. Recent studies have also demonstrated its potentially oncogenic properties in acute lymphoblastic leukaemia, 43 chronic myeloid leukaemia, 44 multiple myeloma, 45 and Burkitt’s lymphoma.…”

OSdlbcl: An online consensus survival analysis web server based on gene expression profiles of diffuse large B‐cell lymphoma

“…Independent validation across different cohorts is of great importance for biomarker development, and OSdlbcl is a web server that could facilitate the cross‐validation of the prognostic value of biomarkers across seven DLBCL cohorts. To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table , Figure ) . The forest plots more effectively presented the comparison results from references and OSdlbcl (Figure ).…”

“…To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table 2, Figure 1). 2,9,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] The forest plots more effectively presented the comparison results from references and OSdlbcl ( Figure S1). Results showed that about 52% (12 out of 23) of biomarkers have significant prognostic values in the combined cohorts, while the remaining biomarkers (11 out of 23) present significant prognostic values in one or more cohorts ( Table 2).…”

Clinical Significance of Circulating Tumor Cells and Ki-67 in Renal Cell Carcinoma

“…Ki67 is a nuclear antigen that is present in almost all human malignancies. A growing body of research on lymphomas, 31 bladder cancer, 32 colorectal cancer 33 and gastric cancer, 34 have shown that overexpression of Ki-67 is associated with tumor cell growth, biological aggressiveness and the prognosis of these malignancies. Moreover, In RCC labeling indexes of Ki67 was found to be positively associated with advanced tumour stage and grade, and provide an additional prognostic indication of biological aggressiveness.…”