Clinical Significance Of LEF1 Expression In Acute Myeloid Leukemia

Objective Lymphoid enhancer-binding factor 1(LEF1) is a downstream effector of Wnt/β-catenin signaling pathway, encoded by gene locating on q23-q25 of chromosome 4. It mediates Wnt signaling through recruiting β-catenin and its co-activators to Wnt response elements of target genes. In the recent years, many studies reported that LEF1 dysregulation is associated with a number of malignant solid tumours and malignant hematological disorders. However, its expression level and pathophysiological role vary in different kinds of diseases. Here, we describe the detailed expression profile of LEF1 in acute myeloid leukemia(AML) and determine its specific prognostic significance in this disease.Methods We used real-time quantitative reverse transcription polymerase chain reaction(RT-PCR) to detect the expression of LEF1 m RNA of bone marrow(BM) samples from 101 patients with previously untreated AML samples and 20 healthy donors. BM samples were collected between April 2008 and August 2012 at the First Affiliated Hospital of Nanjing Medical University. The cytogenetics analysis was performed in 91 AML patients using short-term culture of bone marrow cells and G-banding technique. The genomic DNA was extracted from BM cells and amplified by polymerase chain reaction(PCR). The mutation analysis of NPM1, FLT3-ITD, c-kit and CEBPα gene were performed by DNA sequencing. For quantitative parameters, overall differences between the cohorts were evaluated using a Mann-Whitney U test. Survival analysis was calculated using Kaplan-Meier method.We also studied the prognostic effect of the various clinical variables using multivariate Cox proportional hazards model. All statistical analyses were performed using the SPSS version 17.0 and p<0.05 was considered statistically significant.Results 1. The expression level of LEF1 m RNA in 101 AML patients was significantly higher compared with 20 normal controls(p=0.003). 2. We analyzed LEF1 m RNA expression among subgroups distinguished by clinical characters and known prognostic factors and found that patients with PML-RARα or AML1-ETO had higher LEF1 m RNA level compared with those without these two fusion genes(p=0.014). Patients with favorable risk cytogenetics expressed higher LEF1 m RNA level compared with those with other cytogenetics(p=0.029). 3. We analyzed the relationship between LEF1 m RNA expression and therapeutic response of AML and found that patients with relatively higher LEF1 values were more likely to achieve CR after the initial induction therapy(p=0.034). The LEF1 level were dramatically decreased following successful induction therapy(p=0.012). 4. Among patients with intermediate risk karyotype, high LEF1 m RNA expression was related to a significantly better OS(p=0.019). A scoring system developed based on LEF1 m RNA level and the mutation status of FLT3-ITD or NPM1 indicated that patients with a score of +1 showed a significant better OS compared with those with a score of 0(p=0.015).Conclusions 1. LEF1 m RNA expression is significantly up-regulated in AML patients. 2. Patients with PML-RARα or AML1-ETO fusion genes have relatively high LEF1 expression, indicating that LEF1 may contribute to the pathophysiology of AML with those fusion genes. 3. High LEF1 expression is a favorable prognostic factor among AML patients with intermediate risk karyotype. 4. Our scoring system based on LEF1 level and mutation status of FLT3-ITD or NPM1 is reliable to predict the outcome for AML with intermediate-risk cytogenetics.