Oncotarget

Research Papers:

FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures

Kah Keng Wong, Duncan M. Gascoyne, Elizabeth J. Soilleux, Linden Lyne, Hayley Spearman, Giovanna Roncador, Lars M. Pedersen, Michael B. Møller, Tina M. Green and Alison H. Banham _

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Oncotarget. 2016; 7:52940-52956. https://doi.org/10.18632/oncotarget.9507

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Abstract

Kah Keng Wong1, Duncan M. Gascoyne2, Elizabeth J. Soilleux2, Linden Lyne2, Hayley Spearman2, Giovanna Roncador3, Lars M. Pedersen4, Michael B. Møller5, Tina M. Green5, Alison H. Banham2

1Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia

2NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

3Monoclonal Antibody Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

4Department of Haematology, Roskilde Hospital, Roskilde, Denmark

5Department of Pathology, Odense University Hospital, Odense, Denmark

Correspondence to:

Alison H. Banham, email: alison.banham@ndcls.ox.ac.uk

Keywords: diffuse large B-cell lymphoma, FOXP2, survival

Received: January 30, 2016     Accepted: May 04, 2016     Published: May 20, 2016

ABSTRACT

FOXP2 shares partially overlapping normal tissue expression and functionality with FOXP1; an established diffuse large B-cell lymphoma (DLBCL) oncogene and marker of poor prognosis. FOXP2 is expressed in the plasma cell malignancy multiple myeloma but has not been studied in DLBCL, where a poor prognosis activated B-cell (ABC)-like subtype display partially blocked plasma cell differentiation. FOXP2 protein expression was detected in ABC-DLBCL cell lines, and in primary DLBCL samples tumoral FOXP2 protein expression was detected in both germinal center B-cell-like (GCB) and non-GCB DLBCL. In biopsies from DLBCL patients treated with immunochemotherapy (R-CHOP), ≥ 20% nuclear tumoral FOXP2-positivity (n = 24/158) correlated with significantly inferior overall survival (OS: P = 0.0017) and progression-free survival (PFS: P = 0.0096). This remained significant in multivariate analysis against either the international prognostic index score or the non-GCB DLBCL phenotype (P < 0.05 for both OS and PFS). Expression of BLIMP1, a marker of plasmacytic differentiation that is commonly inactivated in ABC-DLBCL, did not correlate with patient outcome or FOXP2 expression in this series. Increased frequency of FOXP2 expression significantly correlated with FOXP1-positivity (P = 0.0187), and FOXP1 co-immunoprecipitated FOXP2 from ABC-DLBCL cells indicating that these proteins can co-localize in a multi-protein complex. FOXP2-positive DLBCL had reduced expression of HIP1R (P = 0.0348), which is directly repressed by FOXP1, and exhibited distinct patterns of gene expression. Specifically in ABC-DLBCL these were associated with lower expression of immune response and T-cell receptor signaling pathways. Further studies are warranted to investigate the potential functional cooperativity between FOXP1 and FOXP2 in repressing immune responses during the pathogenesis of high-risk DLBCL.


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