A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact

作者：Queiros A C; Villamor N; Clot G; Martinez Trillos A; Kulis M; Navarro A; Penas E M M; Jayne S; Majid A; Richter J; Bergmann A K; Kolarova J; Royo C; Russinol N; Castellano G; Pinyol M; Bea S; Salaverria I; Lopez Guerra M; Colomer D; Aymerich M; Rozman M; Delgado J; Gine E; Gonzalez Diaz M; Puente X S; Siebert R; Dyer M J S; Lopez Otin C; Rozman C; Campo E; Lopez Guillermo A^*; Martin Subero J I

来源：Leukemia, 2015, 29(3): 598-605.

DOI：10.1038/leu.2014.252

Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n = 211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P < 0.001) and VH usage (P < 0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P < 0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P < 0.001) along with Binet stage (P < 0.001). These findings were corroborated in a validation series (n = 97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.

• 出版日期2015-3