Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1

Craig, Vanessa J.; Cogliatti, Sergio; Imig, Jochen; Renner, Christoph; Neuenschwander, Stefan; Rehrauer, Hubert; Schlapbach, Ralph; Dirnhofer, Stephan; Tzankov, Alexandar; Müller, Anne

doi:10.1182/blood-2010-10-312231

Cited by 158 publications

(130 citation statements)

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“…FOXP factors regulate cell proliferation in a cell context-dependent fashion [42]. Although regulation of cancer cell proliferation by FOXP1 has not previously been the subject of intensive study, FOXP1 overexpression was detected in gastric diffuse large B cell lymphoma, and FOXP1 knockdown efficiently blocked DLBCL proliferation [43]. In this study, FOXP1 was found to promote estrogen-dependent proliferation of MCF-7 cells, consistent with findings of a positive correlation between FOXP1 immunoreactivity and pT in breast cancer.…”

Section: Discussionsupporting

confidence: 87%

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

et al. 2011

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Breast cancer is primarily a hormone-dependent tumor that can be regulated by the status of steroid hormones, including estrogen and progesterone. Forkhead box P1 (FOXP1) is a member of the forkhead box transcription factor family and has been reported to be associated with various types of tumors. In the present study, we investigated the expression of FOXP1 in 133 human invasive breast cancers, obtained by core biopsy, by immunohistochemical analysis. Nuclear immunoreactivity of FOXP1 was detected in 89 cases (67%) and correlated positively with tumor grade and hormone receptor status, including estrogen receptor alpha (ERα) and progesterone receptor, and negatively with pathological tumor size. In ERα-positive MCF-7 breast cancer cells, we demonstrated that FOXP1 mRNA was upregulated by estrogen and increased ERα recruitment to ER binding sites identified by ChIP-on-chip analysis within the FOXP1 gene region. We also demonstrated that proliferation of MCF-7 cells was increased by exogenously transfected FOXP1 and decreased by FOXP1-specific siRNA. Furthermore, FOXP1 enhanced estrogen response element-driven transcription in MCF-7 cells. Finally, FOXP1 immunoreactivity was sig-

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Section: Discussionsupporting

confidence: 87%

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

et al. 2011

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“…6 We have shown earlier that aberrant FOXP1 expression in ABC DLBCL may alternatively also result from dysregulated posttranscriptional regulation. 7,8 FOXP1 protein levels are regulated by the microRNA miR-34a, which itself is either transcriptionally or epigenetically silenced in nodal and extranodal DLBCL. 7 Therefore, aberrant FOXP1 expression is a common feature of various types of mature B-cell lymphomas that can result from either genetic abnormalities or transcriptional or posttranscriptional dysregulation.…”

mentioning

confidence: 99%

“…7,8 FOXP1 protein levels are regulated by the microRNA miR-34a, which itself is either transcriptionally or epigenetically silenced in nodal and extranodal DLBCL. 7 Therefore, aberrant FOXP1 expression is a common feature of various types of mature B-cell lymphomas that can result from either genetic abnormalities or transcriptional or posttranscriptional dysregulation.FOXP1 expression is a well-documented negative prognostic factor in ABC DLBCL and marginal zone lymphoma that can be used either alone 5,[9][10][11][12] or as part of a biomarker panel. 13,14 The inferior outcome in patients with FOXP1-expressing DLBCL holds true irrespective of gains or structural aberrations at the FOXP1 genomic locus (3p14.1) 5 and for patients treated with CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), alone or in combination with rituximab (R-CHOP).…”

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confidence: 99%

The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling

Flori

Schmid

Sumrall

et al. 2016

Blood

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Key Points• The sphingosine-1-phosphate receptor 2 (S1PR2) is a novel tumor suppressor and survival prognosticator in the ABC subtype of DLBCL.• S1PR2 is a direct, repressed FOXP1 target; ectopic S1PR2 expression induces apoptosis in DLBCL cells in vitro and prevents tumor growth.Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Ga13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor. (Blood. 2016;127(11):1438-1448 IntroductionThe forkhead box protein 1 (FOXP1) transcription factor is aberrantly expressed in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and represents a widely accepted biomarker for survival prognostication in DLBCL. The FOXP1 genomic locus is recurrently targeted by genomic rearrangements in ABC DLBCL as well as in marginal zone lymphoma of mucosa-associated lymphoid tissue and in chronic lymphocytic leukemia, which correlates with a poor prognosis in each disease entity. 1-3 Primary FOXP1 translocations predominantly involve the immunoglobulin heavy chain locus, leading to overexpression of the full-length protein 3 ; in contrast, the rare nonimmunoglobulin rearrangements of FOXP1 generate N-truncated isoforms that are believed to drive disease progression rather than initiation. 4 Most FOXP1-expressing lymphomas exhibit no apparent structural aberrations of the gene 5 ; the short, putatively oncogenic isoforms in particular are highly expressed from the wild-type locus in ABC DLBCL as a consequence of "normal" B-cell activation. 6 We have shown earlier that aberrant FOXP1 expression in ABC DLBCL may alternatively also result from dysregulated posttranscriptional regulation. 7,8 FOXP1 protein levels are regulated by the microRNA miR-34a, which itself is either transcriptionally or ep...

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“…They also participate in the regulation of important signaling pathways, such as NF-B [69], phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/ protein kinase B (also known as AKt) [70], tumor growth factor-(TGF- [71], and BCR signaling [72], and regulate pro-apoptotic proteins, such as Bcl-2 [73], p53 [74] and transcription factors, such as Myc, FoxP1 [75] and Bcl-6 [76]. MALT lymphomas may transform into gastric diffuse large B-cell lymphoma (gDLBCL); however, the mechanisms of this transformation have not been elucidated.…”

Section: Microrna Is Related To Malt Lymphomamentioning

confidence: 99%

“…Craig et al [75] used a microarray approach to compare the microRNA expression profiles of gastric MALT lymphoma and gDLBCL. They found that microRNAs, which were deregulated in high-grade but not low-grade cases, were transcriptionally repressed by Myc.…”

Section: Microrna Is Related To Malt Lymphomamentioning

confidence: 99%

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue—from (auto)antigen driven selection to the activation of NF-κB signaling

Zhang

Wei

et al. 2015

Sci. China Life Sci.

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Lymphomas of mucosa-associated lymphoid tissue (MALT) are typically present at sites such as the stomach, lung or urinary tract, where lymphoid tissues scatter in mucosa lamina propria, intra-or sub-epithelial cells. The infection of certain pathogens, such as Helicobacter pylori, Chlamydophila psittaci, Borrelia burgdorferi, hepatitis C virus, or certain autoantigens cause these sites to generate a germinal center called the "acquired lymphoid tissue". The molecular pathogenesis of MALT lymphoma is a multi-step process. Receptor signaling, such as the contact stimulation of B cell receptors and CD4 positive T cells mediated by CD40/CD40-ligand and T helper cell type 2 cytokines like interleukin-4, contributes to tumor cell proliferation. A number of genetic alterations have been identified in MALT lymphoma, and among them are important translocations, such as t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32). Fusion proteins generated by these translocations share the same NF-B signaling pathway, which is activated by the caspase activation and recruitment domain containing molecules of the membrane associated guanylate kinase family, B cell lymphoma-10 and MALT1 (CBM) protein complex. They act downstream of cell surface receptors, such as B cell receptors, T cell receptors, B cell activating factors and Toll-like receptors, and participate in the biological process of MALT lymphoma. The discovery of therapeutic drugs that exclusively inhibit the antigen receptor signaling pathway will be beneficial for the treatment of B cell lymphomas in the future. malt lymphoma, helicobacter pylori, chromosomal translocation, genetic alteration, NF-B Citation:Zhang YA, Wei Z, Li J, Liu P. Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue-from (auto)antigen driven selection to the activation of NF-B signaling.

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Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1

Cited by 158 publications

References 38 publications

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue—from (auto)antigen driven selection to the activation of NF-κB signaling

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