The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

Wang, Jenny; Krivtsov, Andrei V.; Sinha, Amit; North, Trista E.; Goessling, Wolfram; Feng, Zhaohui; Zon, Leonard I.; Armstrong, Scott A.

doi:10.1126/science.1186624

Cited by 682 publications

(701 citation statements)

References 25 publications

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“…While there are conflicting data on the role of WNT signaling in normal hematopoietic stem cell self-renewal, mouse models have demonstrated that β-catenin is critical for AML stem cell self-renewal. [2][3][4] These data, combined with the clinical observation that increased canonical WNT signaling in AML blasts at diagnosis is associated with decreased rates of relapse-free and overall survival, suggested a potential clinical benefit for WNT suppression. 5,6 While this approach has shown promise in the treatment of AML, haematologica 2015; 100:e49 questions remain as to which subtypes of AML will benefit.…”

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confidence: 93%

“…2,3 It is well known that nuclear translocation of β-catenin in this manner induces target gene transcription through physical interaction with members of the TCF/LEF family of transcription factors. While there are conflicting data on the role of WNT signaling in normal hematopoietic stem cell self-renewal, mouse models have demonstrated that β-catenin is critical for AML stem cell self-renewal.…”

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confidence: 99%

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Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

et al. 2014

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confidence: 93%

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confidence: 99%

Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

et al. 2014

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“…1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common. 3,[5][6][7]21 Short-lived response and development of resistance to first-line immunochemotherapy are major challenges in MCL and new therapeutic strategies are being developed.…”

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confidence: 99%

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

et al. 2013

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Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (b-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by b-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and antiapoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma.

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“…The Wnt signaling pathway is involved in the regulation of certain types of CSCs (15)(16)(17)(18)(19)(20). Additionally, the canonical Wnt signaling is activated in mammary mesenchymal subpopulation cells, but not in the parental cells, in an autocrine manner (33).…”

Section: Discussionmentioning

confidence: 99%

“…The similarities between normal adult stem cells and CSCs suggest that the signaling pathways involved in somatic stem cell maintenance may also be involved in the regulation of CSCs. This assumption is verified in certain CSCs, such as colon (15), prostate (16) and cutaneous cancer (17), chronic myeloid leukemia (18), acute myelogenous leukemia (19) and hepatic carcinoma (20). The Wnt signaling pathway is a highly conserved signaling pathway.…”

Section: Introductionmentioning

confidence: 90%

The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer

Cai

Zhu

2012

Mol Med Report

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Abstract. Cancer stem cells (CSCs) possess the ability of self-renewal and tumor initiation. Targeting key signaling pathways that are active in CSC self-renewal is one approach to cancer therapy. Abnormal activation of the Wnt/β-catenin pathway has been described in a wide variety of human cancers and in CSCs; however, the role of this pathway in gastric CSCs has not been reported. In our study, we investigated whether the Wnt/β-catenin pathway plays an important role in gastric CSCs. First, we isolated cancer stem-like cells (CSLCs) from the human gastric cancer cell line MKN-45 using tumorsphere cultures. We tested whether tumorsphere cells were CSLCs using the following three criteria: i) We identified that the expression of the CSC marker CD44 was significantly greater in tumorsphere cells compared to adherent cells; ii) compared with adherent cells, the floating tumorsphere cells had greater self-renewing capacity; iii) in vivo xenograft studies showed that tumorsphere cells generate larger tumors than adherent cells at the same number. In addition, we studied the mechanism(s) by which the canonical Wnt signaling pathway acts in CSLCs. Western blotting and real-time PCR showed that the expression levels of β-catenin and c-myc, cyclin d1 and axin 2 were downregulated/upregulated with the inhibition/activation of the Wnt pathway. The pathway blocked by DKK-1 caused a higher reduction in the self-renewing capacity of MKN-45 tumorsphere cells and the pathway activated by lithium chloride improved the self-renewal of CSLCs. In conclusion, our data suggested that the Wnt/β-catenin pathway is essential for the self-renewal of CSLCs in human gastric cancer.

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The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

Cited by 682 publications

References 25 publications

Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

Pharmacological targeting of -catenin in normal karyotype acute myeloid leukemia blasts

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

The Wnt/β-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer

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