Lymphoid Enhancer Binding Factor-1 (LEF1) Expression As a Prognostic Factor In Adult Acute Promyelocytic Leukemia

Abstract

Introduction Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/ β-catenin signaling pathway, which controls cell growth and differentiation. In normal hematopoiesis, LEF1 plays a pivotal role in the development of B- and T-lymphocytes as well as granulocyte progenitor cells. High LEF1 expression has been reported as a favorable prognostic marker in cytogenetically normal acute myeloid leukemia whereas it is associated with poor prognosis in adult B precursor acute lymphoblastic leukemia and in chronic lymphocytic leukemia. Moreover, marked downregulation of LEF1 is associated with disease progression in myelodysplastic syndromes. Given the functional role of LEF1 in hematopoiesis and its putative prognostic impact in several hematological malignancies, we evaluated the prognostic significance of LEF1 expression in adult acute promyelocytic leukemia (APL). Methods One hundred and three consecutive patients with newly diagnosed APL were observed and treated with ATRA-based regimens (AIDA04937 and AIDA2000 GIMEMA protocols), between January 1996 and December 2012. LEF1 expression was measured by real-time qPCR in 78 patients (median age 45 years, range 16 to 88 years) with sufficient available material from the primary cohort. Advanced relative quantification analysis was performed using LightCycler 480 Software 1.5.1, based on the ΔΔCt method. APL samples were dichotomized at the median value and divided into two expression groups: low LEF1 (39 patients) with LEF1 values below the median value (LEF1low) and high LEF1 (39 patients) with LEF1 values above the median value (LEF1high). Clinical and biological features of the two groups were compared. A p value <0.05 was considered significant. Multivariable Cox proportional hazards models were used to study factors (LEF1 expression, FLT3 mutation status, and relapse risk grade) associated with survival endpoints. To evaluate the biological impact of the differential expression of LEF1 in APL, a dataset (GSE13159, including 37 samples of APL patients ) was identified and downloaded from the Gene Expression Omnibus. Results Patients with LEF1high expression had lower white blood cell counts at baseline (1.8 vs 12.0 x109/L; p < 0 .0001), and were less likely to carry a FLT3-ITD than LEF1low patients (12.8% vs 35.9%, respectively, p=0.02). The association between LEF1low and the presence of FLT3-ITD was also confirmed when the 11 patients with FLT3-TKD were included among patients with FLT3 mutations (p=0.03), or the group of FLT3 wild type patients, as compared to those bearing FLT3-ITD (p=0.03). Early death (defined as death during induction treatment) occurred in nine cases (23%) of the LEF1low group versus no case in the LEF1high group (OR = 0.04; p= 0.002). LEF1low expression was associated with a high relapse risk score (53.9% vs 7.7%, OR=0.07; p < 0.0001). The LEF1high group showed a trend toward a statistically significant association with a lower median age (p = 0.08). No significant differences were observed regarding CD34, CD2, bcr3 positivity and LEF1 expression. Survival analysis of 61 APL patients < 60 years revealed that the LEF1high group had significantly longer overall survival (OS) (p = 0.03), whereas no differences were observed between the two groups in terms of relapse-free survival. Cox analysis for OS confirmed only LEF1 expression as an independent prognostic factor (HR=5.4; 95% CI, 1.0 – 27.5, p =0.04). Among the 17 patients over the age of 60, those with LEF1high expression showed a higher median survival than those in the LEF1low group (6.5 vs 0.04 y.rs, p = 0.05). In silico analysis of the differential expression of LEF1 in APL identified 9 differentially expressed, up-modulated genes associated with a high expression of LEF1 (ETS1, FAIM3, CCR7, IL7R, LCK, IL2RB, ITK, RASGRP1, TRBC1); the majority of these genes is involved in the regulation of apoptosis Conclusions Our study provides, for the first time, evidence that LEF1 expression is an independent prognostic factor in APL and that it could be used in patients risk stratification. The observation provided by in silico gene expression analysis that LEF1 expression in APL is associated with biologic changes, mostly in terms of apoptosis regulation, will need to be confirmed experimentally. Disclosures: No relevant conflicts of interest to declare.

Overexpression of lymphoid enhancer‐binding factor‐1 (LEF1) is a novel favorable prognostic factor in childhood acute lymphoblastic leukemia

“…Previous study suggests a possible link between the degree of LEF1 overexpression and poor prognosis in adult B-precursor ALL [25] and chronic lymphocytic leukemia [26]. However, a more recent study showed that high LEF1 level is a favorable prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML) [23], AML [24], and acute promyelocytic leukemia (APL) [34] of adult patients. Here, our study reports that high LEF1 expression is associated with favorable CR rate and OS in childhood ALL.…”

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

“…LEF‐1 upregulation in RUNX1 / RUNX1T1 or PML ‐ RARα and normal karyotype AML is associated with favorable prognosis 74‐76 …”

“…LEF1 up‐regulation was reported in RUNX1‐RUNX1T1 and PML ‐ RARα AML, as well as in cases with normal karyotype and was associated with better prognosis 74‐76 . More recently, a detailed analysis of LEF1 isoforms showed that AML cells predominantly express the long isoform, which is able to bind β‐catenin, while normal HSC expresses the short LEF1 variant, which lacks the N‐terminal and its β‐catenin binding site 77 .…”

“…129 Overexpression of LEF-1 LEF-1 upregulation in RUNX1/RUNX1T1 or PML-RAR and normal karyotype AML is associated with favorable prognosis. [74][75][76] Overexpression of LEF-1 was detected in AML blasts from blood and bone marrow 77,81 and promoted nuclear localization of -catenin. 78 LEF-1 high expression is associated with high-risk leukemia factors in adult BCP-ALL.…”

Downregulation of LEF1 Impairs Myeloma Cell Growth Through Modulating CYLD/NF-κB Signaling

“…7,8 In acute promyelocytic leukemia (APL) patients, high LEF1 expression was also associated with better prognosis. 9 In contrast, the expression pattern as well as potential role of LEF1 in MM remains largely unexplored in multiple myeloma. Based on a relatively limited number of clinical samples, we have previous reported 10 that LEF1 was highly expressed in malignant plasma cells from MM patients as compared to that in normal plasma cells from healthy volunteers; and more importantly, MM patients exhibiting high LEF1 expression had a reduced overall survival than those with low LEF1 expression.…”