FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures.
Wong, Kah Keng
Gascoyne, Duncan M
Pedersen, Lars M
Møller, Michael B
Green, Tina M
Banham, Alison H
Impact Journals, LLC
MetadataShow full item record
Wong, K. K., Gascoyne, D. M., Soilleux, E., Lyne, L., Spearman, H., Roncador, G., Pedersen, L. M., et al. (2016). FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures.. Oncotarget, 7 (33), 52940-52956. https://doi.org/10.18632/oncotarget.9507
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.
Cell Line, Tumor, Humans, Cyclophosphamide, Vincristine, Doxorubicin, Prednisone, Repressor Proteins, Antineoplastic Combined Chemotherapy Protocols, Gene Expression Profiling, Signal Transduction, Gene Expression Regulation, Neoplastic, Protein Binding, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Forkhead Transcription Factors, Lymphoma, Large B-Cell, Diffuse, Young Adult, Kaplan-Meier Estimate, Antibodies, Monoclonal, Murine-Derived, Transcriptome, Gene Ontology
External DOI: https://doi.org/10.18632/oncotarget.9507
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287122
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/