Prognostic evidence of LEF1 isoforms in childhood acute lymphoblastic leukemia

Abstract

Introduction The lymphoid enhancer factor 1 (LEF1) is a DNA‐binding transcription factor that functions in the Wnt signaling pathway. Increased LEF1 activity is associated with progression of several types of cancer including leukemia. Here, we investigated LEF1 isoform expression and genomic variations in acute lymphoblastic leukemia (ALL). Methods LEF1 isoform expression was evaluated by quantitative real‐time PCR in 87 newly diagnosed childhood ALL patients and controls. Moreover, Western blot analysis was performed for detection of LEF1 expression and the hotspot region of LEF1 was screened by deep sequencing. Results The LEF1 mRNA expression of B cell ALL patients was higher than the controls (LEF1‐total P = .011, LEF1‐long P = .026). Moreover, B‐ALL samples showing higher total LEF1 expression had significantly shorter relapse‐free survival (P = .008) and overall survival (P = .011). Although full‐length LEF1 expression was similar to the controls in T‐ALL, 50% (n = 15) of the ALL patients had increased full‐length LEF1 protein expression. Imbalance between short‐ and full‐length LEF1 isoforms may lead to cell survival in ALL. Beside the LEF1 activation, LEF1 gene variations were rarely observed in our cohort. Conclusion The results indicate that the Wnt pathway may have a pathogenic function in a group of ALL patients and high LEF1‐total expression might be a marker for shorter relapse‐free survival time in B cell ALL.

Differential Expression of LEF1 Isoforms in Adult Lymphoid and Myeloid Malignancies

“…In our previous study, we showed that pediatric ALL patients have increased FL-LEF1 expression and an abnormal ratio of long and short LEF1 isoforms have been found in B and T cell ALL (13). Here we defined the different expression patterns of LEF1 isoforms among adult lymphoid and myeloid malignancies and showed that although lymphoid and myeloid malignancies had significantly increased LEF1 expression, lymphoid group patients have significantly aberrant LEF1 activity according to the myeloid patients' group.…”

“…Our previous study showed that pediatric T-cell and B-cell ALL patients have differential expression of LEF1 variants (13). Therefore, in this study, we focused on LEF1 isoforms' expression in a group of adult lymphoid and myeloid hematological malignancies and found tissue-specific differential expression for LEF1 gene variants.…”

“…To measure the balance between the isoforms, the ratio of T-LEF1/ FL-LEF1 was also calculated for each hematologic malignancy. The primer sequences of LEF1 isoforms and the qRT-PCR protocol were shown previously (13). CYPA and BACT genes were used as housekeeping genes.…”

Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a-/- T Acute Lymphoblastic Leukemia

“…Other murine models of T-ALL, including those arising in Tcf7 -/and Ikzf1 -/mice also show increased expression of Lef1 (32,33). Recently, a study of childhood ALL, including 28 patients with T-ALL, revealed a positive prognostic value to high LEF1 expression and a second study confirmed this for specific LEF1 isoforms (34,35). However, in a study of adult T-ALL, 25% of patients had elevated expression of LEF1 that was associated with a poor prognosis (36).…”

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

“…Among the identified cancers, over ten high-incidence malignancies result from abnormal activation of the Wnt signaling pathway, including colorectal cancer, 7 lung cancer, 8 breast cancer, 9 and childhood acute lymphoblastic leukemia. 10 Several studies have confirmed that Wnt signaling pathway imbalance can facilitate oral cancer development, 11 and its abnormal activation can directly influence the prognosis of patients with oral cancer. 2 …”