Lef1 Contributes to the Differentiation of Bulge Stem Cells by Nuclear Translocation and Cross-Talk with the Notch Signaling Pathway

Zhang, Yi; Yü, Jin; Shi, Chunying; Huang, Yaqin; Wang, Yun; Yang, Tian; Yang, Jin

doi:10.7150/ijms.5693

Cited by 47 publications

(35 citation statements)

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“…The recent discovery made during a study of the mechanisms at the basis of the differentiation of bulge stem cells is intriguing. Indeed, it has been observed that LEF1 crosstalks with the Notch signaling pathway, as JAG1 is its downstream target [34]. This information is particularly relevant because it is known that JAG1 is more strongly expressed in APL than in other AML subtypes [35] and that it is rapidly downregulated by ATRA treatment of NB4 cells and primary APL blasts [36,37].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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: LEF1low and LEF1high. LEF1high patients had lower WBC counts at baseline and were less likely to carry a FLT3 -ITD than LEF1low patients. Early death occurred only in the LEF1low group. Moreover, LEF1low expression was associated with a high Sanz score. Survival analysis of 61 APL patients < 60 years revealed that the LEF1high 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 LEF1high 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…β‐catenin is stored in the nuclei of anagen hDPCs and stimulates growth signals to activate hair follicle morphogenesis or growth. LEF‐1, one of the key mediators in the Wnt/β‐catenin pathway, plays an important role in regulating the interaction between the epidermis and dermis in hair follicles and is critical to the differentiation of bulge stem cells . For example, LEF‐1 overexpression in bulge stem cells increases β‐catenin translocation into the nucleus to activate target genes of the Wnt pathway, resulting in hair shaft precursor cell differentiation in the hair matrix .…”

Section: Discussionmentioning

confidence: 99%

Boehmite enhances hair follicle growth via stimulation of dermal papilla cells by upregulating β‐catenin signalling

Bak

Lee

et al. 2019

Experimental Dermatology

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Hair growth, a complex process, has long been the subject of intense research. Recent developments in material technology have revealed boehmite as a new therapeutic modality for use in wound healing and scar reduction, indicating its beneficial effects. Nonetheless, the biological bases of the beneficial effects of boehmite remain unknown. We investigated the hair growth properties of boehmite in vitro and in vivo and observed dose‐dependent proliferation of human dermal papilla cells (hDPCs) in vitro and hair regrowth in a mouse model. To investigate the effects of boehmite on the promotion of cell transition to the anagen phase, we evaluated hDPC viability, alkaline phosphatase (ALP) activity, protein expression and vascular endothelial growth factor (VEGF) secretion in vitro and assessed the anagen‐promoting effects of boehmite via gross observation and histological analysis in a mouse model. Boehmite increased hDPC viability, ALP activity, AKT/GSK3ß/ß‐catenin pathway activity, anagen‐related gene expression and VEGF secretion; moreover, it accelerated hair regrowth in a catagen‐anagen transition model via upregulation of β‐catenin signalling and follicular cell proliferation. Collectively, our results indicate that boehmite accelerates hair growth, partly via its effects on critical events in the active phase of the hair follicle cycle, including the promotion of the proliferation of hDPCs and their immediate progeny to the follicle base.

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Section: Discussionmentioning

confidence: 99%

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

Anelli

Zagaria

Minervini

et al. 2013

Blood

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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.

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Lef1 Contributes to the Differentiation of Bulge Stem Cells by Nuclear Translocation and Cross-Talk with the Notch Signaling Pathway

Cited by 47 publications

References 46 publications

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

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

Boehmite enhances hair follicle growth via stimulation of dermal papilla cells by upregulating β‐catenin signalling

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

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