Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10750
FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures.
Oncotarget . 2016 ;7(33):52940-52956.
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.
TRANSCRIPTION FACTOR FOXP2; | CLASS-II EXPRESSION | NF-KAPPA-B | DOWN-REGULATION | PROTEIN HIP1R | GENE | SURVIVAL | BLIMP-1 | DIFFERENTIATION | LYMPHOCYTES
Adult | Aged | Aged, 80 and over | Antibodies, Monoclonal, Murine-Derived | Antineoplastic Combined Chemotherapy Protocols | Cell Line, Tumor | Cyclophosphamide | Doxorubicin | Female | Forkhead Transcription Factors | Gene Expression Profiling | Gene Expression Regulation, Neoplastic | Gene Ontology | Humans | Kaplan-Meier Estimate | Lymphoma, Large B-Cell, Diffuse | Male | Middle Aged | Prednisone | Protein Binding | Repressor Proteins | Signal Transduction | Transcriptome | Vincristine | Young Adult