High Expression of Lymphoid Enhancer-Binding Factor 1 (LEF1) Is Related to Ummutated Status of Igvh and Is an Unfavorable Prognostic Marker for Aggressive CLL Patients
Authors: Wu Wei , Zhu Huayuan , Fu Yuan , Xu Jiadai , Shen Wenyi , Xu Wei , Liu Peng , Li Jianyong 
Published: October 2019

Abstract
Abstract 4573
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B lymphocytes. CLL is highly variable and heterogeneous in clinical courses, prognosis and outcomes, so efficient prognostic markers are essential to better identify different clinical courses of CLL. The prognostic influence of mutations in IGVH, NOTCH1, and other genes, as well as high expression of CD38 and ZAP70 has been identified in recent years. However, these prognostic markers are still not enough to accurately evaluate clinical courses and outcomes of CLL patients. The canonical Wnt pathway is widely involved in multiple physiological and pathological processions. As a member of the TCF/LEF family, lymphoid enhancer-binding factor-1 (LEF1) plays a critical role in Wnt pathway by directly interacting with β-catenin. LEF1 has a regulatory effect in cell proliferation, development and apoptosis of hematopoietic tissues, especially lymphoid lineages. Recent reports identified the potential participation of LEF1 in the pathogenesis of both B-cell and T-cell acute lymphoblastic leukemia. In CLL, it has been demonstrated that LEF1 is significantly overexpressed, and serves as a prosurvival factor for CLL cells.
In the present study, we analyzed the relevance of LEF1 expression with clinical characteristics and outcomes in a cohort of 100 CLL patients. All the patients were previously untreated, or did not receive any treatment in the latest 6 months. The median age was 69 years. LEF1 expression was assessed using quantitative real-time PCR and β-actin mRNA served as an inner control gene. We found that LEF1 expression was significantly relevant with the somatic mutation status of IGVH (P<0.05). In patients with unmutated IGVH, LEF1 expression level was far higher than patients with mutated IGVH. We also found a correlation between LEF1 expression and ZAP70 protein expression. LEF1 mRNA expression level is higher among ZAP70-positive patients. However, this correlation is not statistically significant. No obvious association between LEF1 expression and CD38 was found. Patients were classified into high and low LEF1 subgroups according to a LEF1 media split. Then we analyzed LEF1 effect on overall survival (OS) in CLL patients in different clinical stages classified according to Binet or Rai staging system. Among patients in Binet C stage, high LEF1 expression predicted a shorter OS compared with low LEF1 patients (median, 120 months vs. undefined, P<0.05). For patients staging in Rai III-IV, patients with high LEF1 expression had a much shorter OS than low LEF1 patients (median, 108 months vs. undefined, P<0.05). As CLL patients generally share a relative longer term of survival, we concentrated mainly on the patients with a follow-up for more than 24 months for survival analysis. Low LEF1 patients, compared with high LEF1 patients, had a prolonged overall survival (undefined vs. 144 months; P=0.068). Although the correlation between LEF1 expression and overall survival did not get statistically significance yet, the correlation is quite obvious, indicating the prognostic potential of LEF1 for CLL patients.
In summary, our data showed that LEF1 expression level is significantly correlated with IGVH mutation status. High LEF1 level is an unfavorable prognostic marker for CLL patients in aggressive stages and patients with a long clinical course. The results suggest that LEF1 may be involved in the pathological process of CLL and has the potential for serving as a prognostic marker of CLL.

Disclosures:
No relevant conflicts of interest to declare.