LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells

Morgan, Rhys G.; Ridsdale, Jenna; Payne, Megan; Heesom, Kate J; Wilson, Marieangela C.; Davidson, Andrew D.; Greenhough, Alexander; Davies, Sara; Williams, Ann C.; Blair, Allison; Waterman, Marian L.; Tonks, Alex; Darley, Richard Lawrence

doi:10.3324/haematol.2018.202846

Cited by 36 publications

(48 citation statements)

References 61 publications

(82 reference statements)

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“…Since β-catenin is relevant for the growth and survival of leukemic cells [3,4,5,6,7,8,9], we tested whether LBH589 alters the expression of this protein in leukemic cells. Western blot analyses of MV4-11 and HEL cells revealed that β-catenin was significantly degraded after incubation with LBH589.…”

Section: Resultsmentioning

confidence: 99%

“…The transcription factor β-catenin appears as an actionable drug target in AML, because the expression and activity of β-catenin is linked to disease initiation, unfavorable karyotypes, and poor prognosis. Cells from such patients show enhanced self-renewal capacity, which suggests that β-catenin contributes to a stemness phenotype [3,4,5,6,7,8,9]. Moreover, β-catenin is expressed at significantly higher levels in AML compared to acute lymphoblastic leukemia and β-catenin was found to be overexpressed in 16/25 and 13/59 primary AML samples [5,6].…”

Section: Introductionmentioning

confidence: 99%

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HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

Beyer

Romański

Mustafa

et al. 2019

Cancers

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Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors β-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of β-catenin. Indomethacin destabilizes β-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of β-catenin by WT1. In conclusion, reduced levels of β-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

Beyer

Romański

Mustafa

et al. 2019

Cancers

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“…LEF-1, the transcriptional factor of β-catenin is frequently overexpressed in AML [20,21,22]. Primary AML samples with t(8;21) or t(15;17) express higher levels of LEF-1 than those without either translocation [20] although another study found high LEF-1 expression also in a subset of cytogenetically normal AML patients [21].…”

Section: Wnt Signalling In the Pathogenesis Of Acute Myeloid Leukamentioning

confidence: 99%

Wnt Signalling in Acute Myeloid Leukaemia

Gruszka-Westwood

Valli

Alcalay

2019

Cells

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Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.

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“…After translocation to the nucleus, unphosphorylated β-catenin can associate with the cotranscriptional regulator T-cell factor (TCF)/lymphoid enhancer factor (LEF) and promote the overexpression and activation of proto-oncogenic Wnt target genes such as c-Myc, Cyclin D1 and survivin. 6,7 Accumulating evidence shows that leukemia stem cells (LSCs) drive the initiation and perpetuation of AML as well as chemotherapeutic resistance. LSCs are also the major clinical factors in disease progression and relapse.…”

Section: Introductionmentioning

confidence: 99%

<p>γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/β-Catenin Axis</p>

Qian¹,

Huang²,

Zhang³

et al. 2020

OTT

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Background: Canonical Wnt/β-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of β-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates β-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment. Methods: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and β-catenin was examined via immunofluorescence with a confocal laser scanning microscope. Results: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked β-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited β-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3β (whose effect on β-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition. Conclusion: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3β-mediated nuclear localization of β-catenin-and indicate that targeting γ-catenin might offer new AML treatments.

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LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells

Cited by 36 publications

References 61 publications

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

Wnt Signalling in Acute Myeloid Leukaemia

<p>γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/β-Catenin Axis</p>

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