High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma

Ge, Xueling; Lv, Xiao; Li, Feng; Liu, Xiaoqian; Wang, Xin

doi:10.3892/mmr.2012.835

Cited by 18 publications

(15 citation statements)

References 26 publications

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“…The abundance of specific splice variants of FOXP1 is thought to figure prominently in determining its impact on cancer initiation and progression, although the correlative studies of FOXP1 expression in cancer must be interpreted with caution, as most did not quantify isoform-specific expression. Our mouse xenograft study suggests that FOXP1 isoform 1 promotes tumor growth, a result consistent with the oncogenic functions of Wnt signaling in epithelia cancers and lymphoma (44, 51). In agreement with our result, diagnostic chromosomal translocations place the FOXP1 gene downstream of strong immunoglobulin heavy chain ( IG ) promoters in some DLBCL tumors, resulting in increased abundance of FOXP1 isoform 1 (68).…”

Section: Discussionsupporting

confidence: 79%

“…β-catenin protein abundance positively correlates with DLBCL disease progression, which is consistent with its oncogenic role in many epithelial tumors (44). Therefore, we speculated that FOXP1 might promote Wnt/β-catenin signaling in human DLBCL.…”

Section: Resultssupporting

confidence: 64%

“…Comparatively, the impact of Wnt signaling in lymphoma is less understood, although various studies suggest increased Wnt signaling in at least a subset of DLBCL patients (44, 48-51). First, increased nuclear β-catenin protein, a marker of Wnt pathway activation, is detected in some DLBCL tumors, which correlates with poor outcome (44). Second, Wnt3a-dependent signaling within and between clonal cell populations in DLBCL maintains population equilibrium; preventing Wnt signaling in this context results in decreased cell growth and colony formation (51).…”

Section: Discussionmentioning

confidence: 99%

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FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma

et al. 2015

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The transcription factor FOXP1 is a master regulator of stem and progenitor cell biology. In diffuse large B-cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased FOXP1 protein abundance in DLBCL predicts poor prognosis and resistance to therapy. To connect gene overexpression with phenotype, we developed a genome-wide mass spectrometry-coupled gain-of-function genetic screen, revealing that FOXP1 potentiates β-catenin-dependent Wnt signal transduction. Gain-of-function and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved co-activator of Wnt signaling. In a Wnt-dependent fashion, FOXP1 co-complexed with β-catenin, TCF7L2, and the acetyltransferase CBP, and bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors and knockdown of FOXP1 or Wnt signaling slowed xenograft tumor growth. These data connect FOXP1 overexpression with β-catenin-dependent signal transduction, and provide a new molecular rationale for Wnt-directed therapy in DLBCL.

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Section: Discussionsupporting

confidence: 79%

Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma

et al. 2015

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“…In line with a previous report, we could detect enhanced β-catenin protein expression in a subset of DLBCL biopsies. 38 However, Ge et al found β-catenin largely in the nucleus of DLBCL cells and we detected predominantly cytosolic staining in the ABC DLBCL cell lines and DLBCL biopsies. The positive β-catenin staining in DLBCL resembled the perinuclear or diffuse localization observed in lymphocytes or chronic lymphocytic leukemia cells.…”

Section: Discussioncontrasting

confidence: 56%

Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

et al. 2016

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Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.

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“…FOXP1 is an enhancer of WNT/beta-catenin pathway transduction (Walker et al, 2015). Several studies have shown that WNT/beta-catenin pathway is increased in DLBCLs (Ge, Lv, Feng, Liu, and Wang, 2012;Koch et al, 2014;Qiang, Endo, Rubin, and Rudikoff, 2003;Reya et al, 2000;Staal et al, 2001).…”

Section: Canonical Wnt/beta-catenin Pathwaymentioning

confidence: 99%

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas

Vallée¹,

Lecarpentier²,

Vallée³

2019

Current Issues in Molecular Biology

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Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have s h o w n t h a t cM y c p r o t e i n e x p r e s s i o n i s overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/betacatenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

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High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma

Cited by 18 publications

References 26 publications

FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma

FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma

Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas

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