title: Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients.
abstract: We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.
authors.affiliation: 1] NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK [2] Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
authors.forename: K K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Gascoyne
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Soilleux
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Snell
authors.affiliation: Centre for Human Proteomics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: L
authors.initials: L
authors.lastname: Lyne
authors.affiliation: 1] NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK [2] Biodonostia Research Institute, San Sebastian, Spain [3] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: C H
authors.initials: CH
authors.lastname: Lawrie
authors.affiliation: Department of Pathology and Experimental Therapeutics, Centre for Lymphoid Cancer, BC Cancer Agency and BC Cancer Research Centre, Vancouver, Canada.
authors.forename: R D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Haematology, Roskilde Hospital, Roskilde, Denmark.
authors.forename: L M
authors.initials: LM
authors.lastname: Pedersen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: M B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Pulford
authors.affiliation: 1] Centre for Human Proteomics, Royal College of Surgeons in Ireland, Dublin 2, Ireland [2] School of Biological Sciences, Dublin Institute of Technology, Dublin 8, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: T M
authors.initials: TM
authors.lastname: Green
authors.affiliation: NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Banham
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000069283:Rituximab; D016896:Treatment Outcome; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058846:Antibodies, Monoclonal, Murine-Derived; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C489537:HIP1R protein, human; D008840:Microfilament Proteins; C571759:R-CHOP protocol; D012097:Repressor Proteins; D033921:Vesicular Transport Proteins; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone