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The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.

Original publication

DOI

10.1038/leu.2015.299

Type

Journal article

Journal

Leukemia

Publication Date

03/2016

Volume

30

Pages

605 - 616

Addresses

NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Keywords

Germinal Center, B-Lymphocytes, Humans, Cyclophosphamide, Vincristine, Doxorubicin, Prednisone, Trans-Activators, Nuclear Proteins, Repressor Proteins, RNA, Small Interfering, Antineoplastic Combined Chemotherapy Protocols, Antigens, Differentiation, B-Lymphocyte, Histocompatibility Antigens Class II, Neoplasm Staging, Survival Analysis, Lymphocyte Activation, Signal Transduction, Gene Expression Regulation, Neoplastic, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Forkhead Transcription Factors, Lymphoma, Large B-Cell, Diffuse, Antibodies, Monoclonal, Murine-Derived, HLA-DR alpha-Chains