High Lymphoid Enhancer-binding Factor-1 Research Articles

Aberrant expression of lymphoid enhancer–binding factor 1 in Hodgkin lymphoma

Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor involved in T-cell maturation and is usually absent in mature B cells. Previous studies have shown aberrant LEF1 expression as a sensitive and specific marker in chronic lymphocytic leukemia/small lymphocytic lymphoma. Our primary aims were i) to analyze LEF1 expression in classic Hodgkin lymphomas (CHLs), including de novo and Richter syndrome (RS), and to assess if LEF1 can be a surrogate marker to assess clonal relationship in RSand ii) to compare LEF1 expression in CHL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We included 117 patients: 24 CHL-RS, 66 CHL-de novo, and 27 NLPHL. There was no significant difference in LEF1 expression between CHL-RS and CHL-de novo (79.2% vs 87.9%, P=0.299)or in type I and type II CHL-RS (75% vs 81.3%, P=1.000). However, CHL showed a significantly higher LEF1 expression than NLPHL (85.6% vs 44.4%, P<0.0001). As the Wnt/β-catenin pathway directly regulates LEF1 expression in a β-catenin-dependent way, β-catenin expression was assessed in 76 cases and all were negative. Additionally, no association between Epstein-Barr virus positivity and LEF1 expression was detected. Overall, our findings show high LEF1 expression in CHL, regardless of RS or de novo, indicating LEF1 cannot be utilized as a surrogate marker to suggest clonal relationship in RS. Compared with CHL, LEF1 expression is significantly less common in NLPHL, further attesting that they are biologically distinct entities. The absent β-catenin expression suggests LEF1 expression is independent of Wnt/β-catenin signaling pathway in Hodgkin lymphomas.

High expression of LEF1 correlates with poor prognosis in solid tumors, but not blood tumors: a meta-analysis.

Background: Previously published studies have indicated that lymphoid enhancer-binding factor 1 (LEF1) expression could be recognized as a valuable biomarker to evaluate clinical outcome for various types of malignant cancer, but the results remained controversial. Therefore, we conducted this meta-analysis to pool the published estimates and discuss the relationship of LEF1 expression with cancer prognosis. Methods: Five electronic databases Pubmed, Web of Science, Embase, CNKI, and Wanfang were systematically searched for eligible literatures. Hazard ratios (HRs) and 95% confidence intervals (CIs) from the included studies were combined to estimate the effect of LEF1 expression on cancer patients’ survival. Results: Eleven original studies met the criteria and were enrolled for analysis. The results indicated that compared with patients in low LEF1 expression group, patients in high LEF1 expression group tended to have shorter overall survival (HR = 1.74, 95% CI: 1.06–2.86, P=0.029), especially for patients with solid tumors (HR = 2.39, 95% CI: 1.86–3.08, P=0.000). Conclusions: Individual evidence about the prognostic value of LEF1 expression in human cancers was limited. Our meta-analysis supported the suggestion that elevated LEF1 expression could function as a promising biomarker to predict the clinical outcomes for malignant cancers, especially solid tumors. More high-quality clinical studies are warranted to highlight the prognostic value of LEF1 expression in human cancers.

Lymphoid enhancer-binding factor 1 (LEF-1): a favorable prognostic factor in adult acute myeloid leukemia in Egyptian patients

BackgroundCanonical wingless-type (Wnt) signaling is a crucial pathway involved in normal hematopoiesis and the self-renewal process of hematopoietic stem cells. Deregulation of this pathway has been associated with different subtypes of leukemia. Lymphoid enhancer-binding factor 1 (LEF-1) is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation and granulopoiesis. High LEF-1 expression has been reported as a prognostic marker in several types of adult hematological malignancies. We aimed to assess the prognostic utility of LEF-1 expression in adult de novo acute myeloid leukemia (AML) Egyptian patients in continuation of our previous work. LEF-1 expression was analyzed by real-time polymerase chain reaction (PCR) in 30 adults with newly diagnosed AML and remeasured at day 28 after induction therapy with the assessment of remission status.ResultsPatients were classified according to median expression level into high and low LEF-1 expression groups. LEF-1 levels were dramatically decreased following successful induction therapy. Also, high LEF-1 expression patients had a better response to therapy with better overall survival. ROC curve analysis of LEF-1 expression yielded a cutoff value of < 10.11 log10 (sensitivity of 90.48% and specificity of 100%) for predicting poor outcome. Univariate logistic regression analysis showed that for every log10 increase in the LEF-1 expression level, the chance of the patient to achieve hematological remission was increased by 2.29 folds.ConclusionOur study showed preliminary results that overexpression of LEF-1 is a favorable prognostic factor in newly diagnosed adult AML patients. The prognostic value of LEF-1 could suggest its utility for further risk classifications of AML and potentiality for being a target for therapy.

Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

Heparanase (HPSE) is the only endo-β-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory elements and mining public microarray datasets, we identified SMAD family member 4 (Smad4) as a crucial transcription regulator of HPSE in NB. We demonstrated that Smad4 repressed the HPSE expression at the transcriptional levels in NB cells. Mechanistically, Smad4 suppressed the HPSE expression through directly binding to its promoter and repressing the lymphoid enhancer binding factor 1 (LEF1)-facilitated transcription of HPSE via physical interaction. Gain- and loss-of-function studies demonstrated that Smad4 inhibited the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Restoration of HPSE expression prevented the NB cells from changes in these biological features induced by Smad4. In clinical NB specimens, Smad4 was under-expressed and inversely correlated with HPSE levels, while LEF1 was highly expressed and positively correlated with HPSE expression. Patients with high Smad4 expression, low LEF1 or HPSE levels had greater survival probability. These results demonstrate that Smad4 suppresses the tumorigenesis and aggressiveness of NB through repressing the HPSE expression.

High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid.

Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/β-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL.

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

Lymphoid enhancer-binding factor-1 (LEF1) is a target gene and central mediator of the Wnt signaling pathway. High LEF1 expression has been reported as a prognostic marker in several types of hematologic malignancies of adult patients. In this study, LEF1 expression was analyzed by real-time polymerase chain reaction (PCR) in 122 children with newly diagnosed ALL treated on the China NPCAC97 protocols. Patients' samples were dichotomized at the median value of control group and divided into LEF1(low) and LEF1(high) groups. The LEF1 mRNA levels in patients with ALL were significantly higher than those of normal controls, and the LEF1 levels were dramatically decreased following induction therapy. In addition, LEF1(high) patients had lower white blood cell (WBC) count at diagnosis and lower minimal residual disease (MRD) levels at the time of complete remission as compared to LEF1(low) patients. Finally, our studies showed that high LEF1 expression is associated with favorable CR rate and overall survival (OS) in childhood ALL (5-year OS: LEF1(high) 92% vs. LEF1(low) 73%, P = 0.009). High LEF1 level was associated with a favorable relapse-free survival in standard-risk patients and also related to a better OS within the subgroup of patients with BCR-ABL-negative ALL. Overexpression of LEF1 is a favorable prognostic factor in childhood ALL. The prognostic impact of LEF1 may assist treatment stratification and suggest the need of alternative regimens.

Characterization of LEF1 High Expression and Novel Mutations in Adult Acute Lymphoblastic Leukemia.

Aberrant activation of the Wnt pathway plays a pathogenetic role in tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). Lymphoid enhancer binding factor 1 (LEF1), a key mediator of Wnt signaling, has been linked to leukemic transformation, and LEF1 mutations have been identified in T-ALL. Here we found LEF1 is highly expressed in 25.0% adult ALL patients and LEF1 high expression was associated with high-risk leukemia factors (high WBC, Philadelphia chromosome positive, complex karyotype), shorter event-free survival (EFS), and high relapse rates in patients with B-ALL. LEF1 high expression is also associated with high mutation rate of Notch1 and JAK1 in T-ALL. We identified 2 novel LEF1 mutations (K86E and P106L) in 4 of 131 patients with ALL, and those patients with high-risk ALL (high WBC, complex karyotype). These results suggest a role for LEF1 mutations in leukemogenesis. We further explored the effect of the mutations on cell proliferation and found both mutations significantly promoted the proliferation of ALL cells. We also observed the effect of LEF1 and its mutations on the transcription of its targets, c-MYC and Cyclin D1. We found LEF1 increased the promoter activity of its targets c-MYC and Cyclin D1, and LEF1 K86E and P106L mutants further significantly enhanced this effect. We also observed that the c-MYC and Cyclin D1 mRNA levels were significantly increased in patients with LEF1 high expression compared with those with low expression. Taken together, our findings indicate high LEF1 expression and mutation are associated with high-risk leukemia and our results also revealed that LEF1 high expression and/or gain-of-function mutations are involved in leukemogenesis of ALL.

Prognostic significance of lymphoid enhancer-binding factor-1 expression in egyptian adult B-acute lymphocytic leukemia patients.

Objective:Lymphoid enhancer-binding factor-1 (LEF-1) is a key transcription factor of wingless-type (Wnt) signaling in various tumors and it is associated with a number of malignant diseases such as leukemia. We explored the expression profile of LEF-1 in acute lymphoblastic leukemia (ALL) and determined its specific prognostic significance in this disease.Materials and Methods:We studied LEF-1 expression in 56 newly diagnosed B-acute ALL adult patients using real-time quantitative polymerase chain reaction to investigate whether LEF-1 expression was associated with clinical patient characteristics and treatment outcomes. Results:High LEF-1 expression was associated with significantly poorer disease-free survival (p=0.03) and overall survival (p=0.005). Patients with high LEF-1 expression had a significantly higher relapse rate compared with low LEF-1 expression (p=0.01). Conclusion:We provide evidence that high LEF-1 expression is a prognostic marker in adult B-acute ALL patients.

Lymphoid enhancer binding factor-1 (LEF1) expression as a prognostic factor in adult acute promyelocytic leukemia

Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/ β-catenin signaling pathway. High LEF1 expression has been reported as a prognostic marker in hematologic malignancies. We evaluated the prognostic significance of LEF1 expression in 78 adult acute promyelocytic leukemia (APL) patients. APL samples were dichotomized at the median value and divided into: LEF1(low) and LEF1(high). LEF1(high) patients had lower WBC counts at baseline and were less likely to carry a FLT3-ITD than LEF1(low) patients. Early death occurred only in the LEF1(low) group. Moreover, LEF1(low) expression was associated with a high Sanz score. Survival analysis of 61 APL patients < 60 years revealed that the LEF1(high) group had a significantly longer overall survival (OS). Cox analysis for OS confirmed only LEF1 expression as an independent prognostic factor. Of the 17 patients over the age of 60, those in the LEF1(high) group showed a higher median survival. In silico analysis identified 9 differentially expressed, up-modulated genes associated with a high expression of LEF1; the majority of these genes is involved in the regulation of apoptosis. Our study provides evidence that LEF1 expression is an independent prognostic factor in APL, and could be used in patients risk stratification.

Clinical significance of lymphoid enhancer-binding factor 1 expression in acute myeloid leukemia

Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/β-catenin signaling pathway and its dysregulation is associated with a number of malignant diseases such as leukemia. We explored the expression profile of LEF1 in acute myeloid leukemia (AML) and determined its specific prognostic significance in this disease. The LEF1 mRNA level in patients with previously untreated AML was significantly higher than in normal controls. Patients with AML with relatively higher LEF1 expression were more likely to achieve a complete remission (CR) following induction therapy in comparison to those with a lower LEF1 level. Moreover, we provide the first evidence that primary AML samples with AML1–ETO or PML–RARα have a higher LEF1 level compared with those without each fusion gene. High LEF1 expression predicts a significantly better overall survival for patients with intermediate-risk cytogenetics. High LEF1 level was associated with a favorable relapse-free survival in patients with FLT3-ITD wild-type. Finally, a 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. Our results indicate that LEF1 contributes to the pathophysiology of AML and could serve as a novel predictor of better treatment response. LEF1 level may be incorporated into an improved risk classification system for certain specific subtypes of AML.

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

Abstract 4573Chronic 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.

High expression of lymphoid enhancer-binding factor-1 (LEF1) is a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia

AbstractLymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor of Wnt signaling. We recently showed that aberrant LEF1 expression induces acute myeloid leukemia (AML) in mice, and found high LEF1 expression in a subset of cytogenetically normal AML (CN-AML) patients. Whether LEF1 expression associates with clinical and molecular patient characteristics and treatment outcomes remained unknown. We therefore studied LEF1 expression in 210 adults with CN-AML treated on German AML Cooperative Group trials using microarrays. High LEF1 expression (LEF1high) associated with significantly better relapse-free survival (RFS; P < .001), overall survival (OS; P < .001), and event-free survival (EFS; P < .001). In multivariable analyses adjusting for established prognosticators, LEF1high status remained associated with prolonged RFS (P = .007), OS (P = .01), and EFS (P = .003). In an independent validation cohort of 196 CN-AML patients provided by the German-Austrian AML Study Group, LEF1high patients had significantly longer OS (P = .02) and EFS (P = .04). We validated the prognostic relevance of LEF1 expression by quantitative PCR, thereby providing a clinically applicable platform to incorporate this marker into future risk-stratification systems for CN-AML. Gene-expression profiling and immunophenotyping revealed up-regulation of lymphopoiesis-related genes and lymphoid cell-surface antigens in LEF1high patients. In summary, we provide evidence that high LEF1 expression is a novel favorable prognostic marker in CN-AML.

High Lymphoid Enhancer-Binding Factor-1 (LEF1) Expression Is Associated with ZAP70 Positivity, Requirement of Treatment, and Fibromodulin (FMOD) Expression In Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 1715Chronic lymphocytic leukemia has the highest incidence of all leukemias in the western world. It is characterized by accumulation of monoclonal CD5+ B-lymphocytes and has a highly variable clinical outcome. Lymphoid enhancer-binding factor-1 (LEF1) is part of the LEF/TCF transcription factor family which has been shown to play an important role in regulating Wnt-pathway target genes. It is specifically expressed at early stages of B-cell differentiation and is essential for survival and proliferation. LEF1 plays a crucial role in many human cancers and was shown to promote oncogenic transformation and invasiveness of neoplastic diseases. LEF1 has also been shown to be highly overexpressed in CLL. However, the extent of overexpression shows a high variability between patients. The extracellular matrix protein fibromodulin (FMOD) is a tumor-associated antigen and one of the most overexpressed genes in CLL. It was also shown to be associated with p53-mutation and resistance to DNA damage in CLL cells.The aim of this study was to investigate the prognostic relevance of LEF1 and FMOD expression in CLL. Efficiency-corrected quantitative real-time PCR was used to determine LEF1 and FMOD mRNA expression in 120 and 96 primary CLL samples, respectively. The expression of each sample was calibrated against the mean of 7 healthy B-cell samples. In other words, the calibrated mean relative expression ratio (RER) of the healthy B-cells is 1 by definition, and all other RER values are expressed as fold change compared to healthy B-cells. We assessed correlations with the prognostic markers ZAP70 and CD38 as well as with the percentage of lymphocytes in the peripheral blood. We also investigated correlations of LEF1 and FMOD with each other. Moreover, we compared LEF1 and FMOD expression of patients requiring treatment with the expression of patients in recently diagnosed Binet stage A.We determined a 40-fold higher mean LEF1 mRNA expression and a 16-fold higher mean FMOD expression in our CLL patients' samples compared to the healthy B-cell samples (p<0.001). Patients requiring treatment showed a mean LEF1 mRNA relative expression ratio (RER) of 85.61 whereas patients in recently diagnosed Binet stage A had a mean of only 22.01 (p<0.001). Moreover, mean LEF1 RERs were 53.72 and 37.10 in ZAP70-positive and ZAP70-negative patients, respectively (p=0.004). Furthermore, we found a highly significant positive correlation of LEF1 with the percentage of lymphocytes in the peripheral blood (Spearman's rho = 0.440, p<0.001). We also performed a LEF1 median split dividing the patients in high and low LEF1 subgroups. We then compared the percentages of lymphocytes in the peripheral blood in both subgroups. We observed mean lymphocyte percentages of 88.45% and 76.28% in the high versus low LEF1 groups, respectively (p<0.001). However, we did not observe a significant difference in LEF1 expression between CD38-positive and CD38-negative patients. We also found LEF1 and FMOD expression to be highly correlated with each other (Spearman's rho = 0.405, p<0.001). In addition, the mean FMOD RER was 34.14 in the high LEF1 group and only 4.19 in the low LEF1 group (p<0.001). Given the fact that FMOD expression, p53 mutation, and DNA-damage resistance have been found previously to be associated, the LEF1–FMOD correlation is an interesting new finding. Eventually, it may lend additional support to the prognostic relevance of LEF1 overexpression in CLL. FMOD was also significantly higher expressed in patients requiring treatment compared to patients in recently diagnosed Binet stage A (p=0.042). However, we could not observe any significant association of FMOD with ZAP70, CD38 or the percentage of lymphocytes in the peripheral blood.In a nutshell, our results suggest that high LEF1 expression is associated with poor prognosis, high FMOD expression, and the requirement of treatment in CLL. Thus, LEF1 might be involved in the process of disease progression and possibly can serve as a molecular parameter for risk assessment and/or monitoring of CLL. Disclosures:No relevant conflicts of interest to declare.

High Lymphoid Enhancer-Binding Factor-1 Expression Is Associated with Disease Progression and Poor Prognosis in Chronic Lymphocytic Leukemia

We determined lymphoid enhancer-binding factor-1 (LEF1) mRNA expression in 112 chronic lymphocytic leukemia (CLL) samples and assessed correlations with the prognostic markers ZAP70 and CD38, Binet stages, the percentage of lymphocytes in the peripheral blood, and fibromodulin (FMOD) transcripts. The mean LEF1 relative expression ratios (RER) were 53.72 and 37.10 in ZAP70-positive and ZAP70-negative patients, respectively (P=0.004). However, we did not observe a significant difference in LEF1 expression between CD38-positive and CD38-negative patients. Moreover, patients requiring treatment showed a mean LEF1 RER of 85.61 whereas patients in recently diagnosed Binet A stage had a mean of only 22.01 (P<0.001). We also found significant correlations of LEF1 with the percentage of lymphocytes and FMOD expression. Our results suggest that high LEF1 expression is associated with poor prognosis and disease progression. Thus, LEF1 might be involved in the process of disease progression and possibly can serve as a molecular parameter for risk assessment and/or monitoring of CLL.

High Expression of Lymphoid Enhancer-Binding Factor 1 (LEF1) Is a Novel, Favorable Prognostic Marker in Cytogenetically Normal AML and Is Associated with Upregulation of T-Lymphoid Lineage Markers in AML Blasts.

Abstract 398▪▪This icon denotes an abstract that is clinically relevant.In recent years, the classification of cytogenetically normal acute myeloid leukemia (CN-AML) has seen a turnaround from morphological characterisation towards the identification of novel molecular prognostic factors. Besides the well-recognized prognostic influence of mutations in NPM1, CEPBA, FLT3 and other genes, high transcript levels of ERG, MN1 or BAALC recently have been associated with inferior outcome. However, our understanding of the pathogenetic mechanisms that underlie the prognostic relevance of these markers is limited. The canonical WNT signalling pathway not only plays an important role in embryonic development but is also implicated in almost one third of all human cancers including many subtypes of leukemias. Expression of β-catenin, a key player in the WNT pathway, in AML blasts has been associated with enhanced clonogenic potential and inferior patient survival. Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor that directly interacts with β-catenin during WNT signalling. Recently, we showed that Lef-1 is an important regulatory factor in early hematopoiesis and that its constitutive expression in murine hematopoetic cells causes both myeloid and lymphoid acute leukemias, which originate from a leukemic stem cell with lymphoid characteristics (Petropoulos et al., J Exp Med 2008). In the present study, we analysed the association of LEF1 expression with clinical outcomes in a cohort of 210 adult patients (median age, 59 years) with CN-AML. All patients were treated in two consecutive multicenter studies of the German AML Cooperative Group (AMLCG), and the median follow-up for surviving patients was 46 months. LEF1 expression levels were extracted from gene expression profiles (obtained using Affymetrix HG-U133A or HG-U133plus2 oligonucleotide microarrays). Patients were classified as LEF1high or LEF1low according to the median of all samples. We found that LEF1 expression was inversely correlated with the leukocyte count at diagnosis, and the frequency of FLT3 ITD mutations was significantly lower among patients with high LEF1 transcript levels than among those with low LEF1 expression (59% vs. 24%, respectively; P<0.001). LEF1high patients, as compared with LEF1low patients, showed a significantly prolonged overall survival (OS) (median, 36 vs. 8.6 months, P<0.001) and relapse-free survival (RFS) (median, 27 vs. 6.7 months, P<0.001). The correlation of LEF1 transcript levels with OS could not solely be explained by its inverse association with FLT3 ITD status, since in multivariate analyses, high LEF1 expression remained an independent predictor of prolonged OS (hazard ratio for death, 0.59; 95% confidence interval, 0.40 – 0.88; P=0.01) after adjustment for age, FLT3 status, and ERG expression levels. Moreover, there was no statistically significant interaction between the effects of LEF1 expression levels and FLT3 ITD status or treatment group assignment on OS. High LEF1 levels also were predictive of longer RFS (hazard ratio, 0.49; 95% confidence interval, 0.31 - 0.79; P=0.003) after adjustment for age and the NPM1mutant/FLT3 ITDnegative genotype. We then tried to identify genes that are differentially regulated in LEF1high versus LEF1low low patients. Among the genes that showed the most prominent transcriptional upregulation in LEF1high samples, there were several markers of T-lymphoid differentiation (e.g., CD2, CD3, CD5, and the interleukin 2 receptor beta chain). Statistically significant upregulation of the T-lymphoid markers CD2, cyCD3 and CD7 in LEF1high AML was confirmed by immunophenotyping of the leukemic cells. In contrast, there was no correlation between immunologically detected B-lymphoid markers (e.g. CD19, cyCD22, cyCD79a) and the LEF1 expression level. In summary, our data indicate that high LEF1 expression is an independent favorable prognostic marker in CN-AML, and that it is associated with a distinct gene expression profile and immunophenotype, characterized by upregulation of lymphoid cell antigens. Disclosures:No relevant conflicts of interest to declare.