University of Oulu

Kari, EJM, Kuusisto, MEL, Honkavaara, P, et al. Thioredoxin‐1 as a biological predictive marker for selecting diffuse large B‐cell lymphoma patients for etoposide‐containing treatment. Eur J Haematol. 2020; 105: 156– 163.

Thioredoxin‐1 as a biological predictive marker for selecting diffuse large B‐cell lymphoma patients for etoposide‐containing treatment

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Author: Kari, Esa1; Kuusisto, Milla1; Honkavaara, Päivi1;
Organizations: 1Department of Oncology and Radiotherapy, Medical Research Center, University of Oulu, Oulu University Hospital, Oulu, Finland
2Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland
3Medical Informatics and Statistics Research Group, University of Oulu, Oulu, Finland
4Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
5Department of Pathology, North Karelia Central Hospital, Joensuu, Finland
6Department of Oncology, Faculty of Health Medicine, Institute of Clinical Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
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Language: English
Published: John Wiley & Sons, 2020
Publish Date: 2020-09-14


Objective: In diffuse large B‐cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R‐CHOP regimen.

Methods: The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide‐containing high‐dose regimen (n = 37) and etoposide‐containing frontline treatment (n = 69, R‐CHOEP) were studied using immunohistochemical thioredoxin‐1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin.

Results: Thioredoxin‐1 knockdown sensitised DLBCL cells to doxorubicin (P < 0.0001) but decreased etoposide‐induced cell death (P < 0.00001). In DLBCL patients who received etoposide‐containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5‐year overall survival (46% vs 76%, P = 0.026) and disease‐specific survival (68% vs 90%, P = 0.026).

Conclusions: Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R‐CHOP immunochemotherapy.

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Series: European journal of haematology
ISSN: 0902-4441
ISSN-E: 1600-0609
ISSN-L: 0902-4441
Volume: 105
Issue: 2
Pages: 156 - 163
DOI: 10.1111/ejh.13419
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This study was supported by research funding provided by the Cancer Society of Northern Finland to Kuusisto, the Finnish Medical Association Duodecim to Karihtala and Kuittinen and the Finnish Medical Foundation to Kuusisto. Teppo would like to acknowledge the financial support from the Finnish Medical Foundation, the Finnish medical society Duodecim, the Thelma Mäkikyrö foundation and the Finnish Society for Oncology. Kari and Turpeenniemi‐Hujanen would like to acknowledge the financial support provided by the Väisänen Fund in Terttu Foundation.
Copyright information: © 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.