FOXP1 abnormalities in lymphoma: Translocation breakpoint mapping reveals insights into deregulated transcriptional control

Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, UK.
Modern Pathology (Impact Factor: 6.19). 08/2008; 21(7):902-11. DOI: 10.1038/modpathol.2008.74
Source: PubMed


Deregulation of FOXP1 expression plays an important role in lymphoma development although the underlying molecular mechanism is poorly understood. FOXP1 is targeted by chromosome translocations in MALT lymphoma and diffuse large B-cell lymphoma, where high-level protein expression is associated with poor prognosis. Nonetheless, the incidence and nature of FOXP1 abnormalities at both the genetic and protein levels, and their correlation in these lymphomas are not well established. We investigated FOXP1 translocation, copy number change and protein expression in MALT lymphoma (n=321), MALT lymphoma with a diffuse large B-cell lymphoma component (59), nodal diffuse large B-cell lymphoma (64) and extranodal diffuse large B-cell lymphoma (151) by interphase fluorescence in situ hybridization and immunohistochemistry. FOXP1 translocation was found in eight MALT lymphomas and three MALT lymphomas with diffuse large B-cell lymphoma, with all positive cases originating in the stomach. In diffuse large B-cell lymphoma, the translocation was seen in 5 cases originating in the stomach (2), tonsil (1), large intestine (1) and lymph node (1). Immunoglobulin heavy chain gene was the translocation partner in 11 of the 16 positive cases. Fluorescence in situ hybridization mapping revealed FOXP1 breakpoints within the 5' untranslated region of the gene (upstream of exon 6, the first coding exon of full-length FOXP1) in 14 cases, but downstream of exon 6 (most likely upstream of exon 8) in the remaining 2 cases. Three copies of the FOXP1 gene were observed in MALT lymphoma (17%), MALT lymphoma with diffuse large B-cell lymphoma (12%) and diffuse large B-cell lymphoma (32%), including cases with FOXP1 translocation (19%). Immunohistochemistry showed strong/moderate FOXP1 staining in all the cases with FOXP1 translocation. However, FOXP1 expression was independent of FOXP1 translocation or copy number changes. Our findings suggest that (1) FOXP1 translocation may disrupt the full-length FOXP1 transcript and lead to expression of FOXP1 transcript variants with alternate 5' ends and (2) mechanisms other than translocation and copy number changes are also responsible for FOXP1 overexpression in lymphoma.

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    • "Detection of FOXP1 amplification was performed using the SureFISH 3p13 probe to label FOXP1 together with the centromeric SureFISH Chr3 CEP (Agilent Technologies, Cedar Creek, TX, USA). According to the criteria described by Hoeller et al. [17] high- level amplification was defined as presence of >10 gene signals and FOXP1 gains were defined as the presence of tumor cell nuclei with three or more signals exceeding the mean 3 SD [37] of false positive signals from 100 nuclei in the reference controls, i.e., presence of additional FOXP1 gene signals in >11% of evaluated tumor cell nuclei. "
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    PLoS ONE 06/2014; 9(6):e98169. DOI:10.1371/journal.pone.0098169 · 3.23 Impact Factor
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    • "Banham et al. [35] investigated the prognostic importance of FOXP1 protein expression in DLBCL and found that the overall empirical survival curves for the two subgroups based on the expression of FOXP1 are significantly different. Goatly et al. [36] made an attempt to discover the underlying molecular mechanism of FOXP1 expression in lymphoma development by investigating the FOXP1 translocation, copy number change, and protein expression in mucosa-associated lymphoid tissue lymphoma and DLBCL. Korac and Dominis [37] explored the association between FOXP1, BCL2, and BCL6 gene expression in diffuse large B-cell lymphoma tumor cells. "
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    ABSTRACT: A bivariate mixture model utilizing information across two species was proposed to solve the fundamental problem of identifying differentially expressed genes in microarray experiments. The model utility was illustrated using a dog and human lymphoma data set prepared by a group of scientists in the College of Veterinary Medicine at North Carolina State University. A small number of genes were identified as being differentially expressed in both species and the human genes in this cluster serve as a good predictor for classifying diffuse large-B-cell lymphoma (DLBCL) patients into two subgroups, the germinal center B-cell-like diffuse large B-cell lymphoma and the activated B-cell-like diffuse large B-cell lymphoma. The number of human genes that were observed to be significantly differentially expressed (21) from the two-species analysis was very small compared to the number of human genes (190) identified with only one-species analysis (human data). The genes may be clinically relevant/important, as this small set achieved low misclassification rates of DLBCL subtypes. Additionally, the two subgroups defined by this cluster of human genes had significantly different survival functions, indicating that the stratification based on gene-expression profiling using the proposed mixture model provided improved insight into the clinical differences between the two cancer subtypes.
    Human genomics 01/2013; 7(1):2. DOI:10.1186/1479-7364-7-2 · 2.15 Impact Factor
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    • "Recurrent chromosomal translocations targeting the FOXP1, which commonly but not exclusively involve the IGH locus leading to the translocation t(3;14)(p14;q32), have been described in systemic DLBCL and marginal zone lymphomas of mucosaassociated lymphoid tissue (MALT) (Streubel et al., 2005; Wlodarska et al., 2005; Fenton et al., 2006; Goatly et al., 2008). However, the mechanisms by which FOXP1 expression is deregulated in PCLBCL, leg type are largely unknown. "
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