Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Sagaert, Xavier; Paepe, Pascale De; Libbrecht, Louis; Vanhentenrijk, Vera; Verhoef, Gregor; Thomas, José; Włodarska, Iwona; Wolf-Peeters, Christiane De

doi:10.1200/jco.2006.05.6150

Cited by 134 publications

(110 citation statements)

References 38 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…The prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in decisions regarding clinical treatment [26,27]. FOXP1 is targeted by recurrent chromosome translocations, and its overexpression confers a poor prognosis in numerous types of lymphomas [28][29][30][31][32], suggesting that it functions as an oncogene. However, FOXP1 localizes to a tumor suppressor locus at 3p14.1 [10], and loss of FOXP1 expression in breast cancer is associated with a worse outcome [12]; this suggests that FOXP1 functions as a tumor suppressor in other tissue types.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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-

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…FOXP1 is therefore, thought to be an essential participant in the transcriptional regulatory network responsible for B lymphopoiesis and is needed for B-cell differentiation and life-cycle management [16,22]. Several studies have indicated that the expression of FOXP1 in DLBCL is associated with poor clinical outcome [16, 17, Prognostic value of miR-34a and target proteins in gastric lymphomas 439 [23][24][25]. Previous studies with MALT lymphoma indicate that FOXP1 positivity is confined to MALT lymphomas with poor clinical outcome, polymorphic histology, and high risk of transforming into DLBCL [18,26,27].…”

Section: Follow-up and Survivalmentioning

confidence: 99%

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

He¹,

Li²,

Zhang³

et al. 2013

Gastric Cancer

View full text Add to dashboard Cite

Background Mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL), which are the two most common types of gastric lymphomas, have different clinicopathological features and molecular characteristics with distinct clinical outcomes. Tumor suppressor miR-34a connects the p53 network with forkhead box protein 1 (FOXP1) and BCL2. Here, we investigated the prognostic value of these molecules in gastric MALT lymphoma and DLBCL for use in routine clinical practice. Methods Relative miR-34a expression was detected by quantitative reverse transcriptase-polymerase chain reaction in 20 cases of MALT lymphomas and 20 cases of DLBCLs. Tissue microarray, in situ hybridization, and immunohistochemistry analysis were used to examine the expression of miR-34a and its regulated genes, FOXP1, p53, and BCL2 proteins, in 64 patients with gastric MALT lymphoma and in 58 patients with DLBCL. Helicobacter pylori infection, overall survival (OS), and progression-free survival (PFS) were documented. Results The expression level of miR-34a was markedly decreased in MALT lymphomas and DLBCLs compared to normal gastric tissues and peripheral blood mononuclear cells. miR-34a was present in the cytoplasm and nucleus of lymphocytes. Its expression was significantly downregulated in MALT and DLBCL lymphoma tissues, as compared with normal lymphocytes. The expression level of miR-34a in DLBCL was lower than in MALT lymphoma. FOXP1 was found to be positive in 48 %, p53 in 20 %, and BCL2 in 68 % of MALT lymphoma cases. The corresponding positive rates of these markers in DLBCL were 64, 57, and 52 %, respectively. High expression of FOXP1, p53, and BCL2 was seen in stage III and IV of both types of lymphomas. FOXP1, p53, and BCL2 positivity was associated with poor OS with both lymphoma types but OS with DLBCL was significantly lower than with MALT lymphoma. Conclusions Decreased miR-34a expression and increased FOXP1, p53, and BCL2 coexpression to predict a poor OS for MALT lymphoma and DLBCL patients could become very important prognostic markers in daily clinical work. Further investigation of these changes may be of prognostic significance in clinical practice.

show abstract

“…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).…”

Section: Introductionmentioning

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).…”

mentioning

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

View full text Add to dashboard Cite

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...

show abstract

Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Cited by 134 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

Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL

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

Contact Info

Product

Resources

About