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Lymphoma

Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients

Leukemia volume 28, pages 362–372 (2014)Cite this article

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An Erratum to this article was published on 05 February 2014

This article has been updated

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 FOXP1hi/HIP1Rlo 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 FOXP1hi/HIP1Rlo 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.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

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  • 09 October 2013

    This article has been corrected since Advance Online Publication and a erratum is also printed in this issue

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Acknowledgements

We thank Dr Paola Bignone and Dr Bridget Fox for their assistance with generating the HIP1R full-length plasmid construct, and clinical colleagues for access to patients’ samples. This work was funded by Leukaemia and Lymphoma Research, the Julian Starmer-Smith Memorial Fund, Research University grant (Grant no. 1001/PPSP/813054) from Universiti Sains Malaysia, Fundamental Research Grant Scheme (Grant no. 203/PPSP/6171148) from the Ministry of Higher Education Malaysia, Terry Fox Foundation Program Project (Grant no. 019001) from National Cancer Institute of Canada, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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Authors and Affiliations

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

    K K Wong, D M Gascoyne, P J Brown, E J Soilleux, C Snell, L Lyne, C H Lawrie, K Pulford & A H Banham

  2. Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia

    K K Wong

  3. Centre for Human Proteomics, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    H Chen & D Murphy

  4. Biodonostia Research Institute, San Sebastian, Spain

    C H Lawrie

  5. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    C H Lawrie

  6. Department of Pathology and Experimental Therapeutics, Centre for Lymphoid Cancer, BC Cancer Agency and BC Cancer Research Centre, Vancouver, Canada

    R D Gascoyne

  7. Department of Haematology, Roskilde Hospital, Roskilde, Denmark

    L M Pedersen

  8. Department of Pathology, Odense University Hospital, Odense, Denmark

    M B Møller & T M Green

  9. School of Biological Sciences, Dublin Institute of Technology, Dublin 8, Ireland

    D Murphy

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  1. K K Wong
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Correspondence to A H Banham.

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Wong, K., Gascoyne, D., Brown, P. et al. Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients. Leukemia 28, 362–372 (2014). https://doi.org/10.1038/leu.2013.224

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