FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas.

P J Brown,L Lyne,T M Green,M B Møller,S L Felce,E J Soilleux,L M Pedersen,H Spearman,K K Wong,A H Banham,D M Gascoyne

doi:10.1038/leu.2015.299

Abstract

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.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy that represents approximately 40% of all non-Hodgkin’s lymphomas and displays heterogeneous clinical and molecular characteristics
The FOXP1 gene maps to a tumor-suppressor locus at 3p14.1, and a tumorsuppressive role for FOXP1 has been identified in certain malignancies,[5] other studies have suggested an oncogenic role in lymphoma
We have shown that FOXP1 silencing can lead to an increase in surface major histocompatibility complex class II (MHC II) and CD74 in activated B-cell (ABC)-DLBCL

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy that represents approximately 40% of all non-Hodgkin’s lymphomas and displays heterogeneous clinical and molecular characteristics. DLBCL cell-of-origin (COO) groups are characterized by mostly distinct oncogenic pathways; it is important to identify predictive markers in order to enable patients to be subtyped for personalized molecularly targeted therapy and as a useful prognostic marker for response to standard R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). One such marker is FOXP1 (forkhead box P1), a transcription factor belonging to the forkhead box family,[3] that is involved in B-cell development.[4] The FOXP1 gene maps to a tumor-suppressor locus at 3p14.1, and a tumorsuppressive role for FOXP1 has been identified in certain malignancies,[5] other studies have suggested an oncogenic role in lymphoma. Activation-induced short isoforms (FOXP1S)[8] and genetic rearrangements of FOXP1 leading to truncated FOXP1 isoforms[9] may have important biological roles, for example, by altering or interfering with the normal function of the full-length FOXP1 (FOXP1L) protein or by acquiring novel functions

Objectives

Findings

Conclusion