Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2014
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| _version_ | 1826292588013944832 |
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| author | Wong, K Gascoyne, D Brown, P Soilleux, E Snell, C Chen, H Lyne, L Lawrie, C Gascoyne, R Pedersen, L Møller, M Pulford, K Murphy, D Green, T Banham, A |
| author_facet | Wong, K Gascoyne, D Brown, P Soilleux, E Snell, C Chen, H Lyne, L Lawrie, C Gascoyne, R Pedersen, L Møller, M Pulford, K Murphy, D Green, T Banham, A |
| author_sort | Wong, K |
| collection | OXFORD |
| description | 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. © 2014 Macmillan Publishers Limited. |
| first_indexed | 2024-03-07T03:17:00Z |
| format | Journal article |
| id | oxford-uuid:b61f0e9c-f27b-4723-94b6-20e7b8af2ca1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:17:00Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:b61f0e9c-f27b-4723-94b6-20e7b8af2ca12022-03-27T04:38:46ZReciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patientsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b61f0e9c-f27b-4723-94b6-20e7b8af2ca1EnglishSymplectic Elements at Oxford2014Wong, KGascoyne, DBrown, PSoilleux, ESnell, CChen, HLyne, LLawrie, CGascoyne, RPedersen, LMøller, MPulford, KMurphy, DGreen, TBanham, AWe 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. © 2014 Macmillan Publishers Limited. |
| spellingShingle | Wong, K Gascoyne, D Brown, P Soilleux, E Snell, C Chen, H Lyne, L Lawrie, C Gascoyne, R Pedersen, L Møller, M Pulford, K Murphy, D Green, T Banham, A Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title | Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title_full | Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title_fullStr | Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title_full_unstemmed | Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title_short | Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients |
| title_sort | reciprocal expression of the endocytic protein hip1r and its repressor foxp1 predicts outcome in r chop treated diffuse large b cell lymphoma patients |
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