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Thioredoxin‐1 as a biological predictive marker for selecting diffuse large B‐cell lymphoma patients for etoposide‐containing treatment
Author(s) -
Kari Esa Jarkko Mikael,
Kuusisto Milla Elvi Linnea,
Honkavaara Päivi,
Hakalahti Anna,
Haapasaari KirsiMaria,
Bloigu Risto,
Karihtala Peeter,
Teppo HannaRiikka,
Pirinen Risto,
TurpeenniemiHujanen Taina,
Kuittinen Outi
Publication year - 2020
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13419
Subject(s) - etoposide , medicine , vincristine , diffuse large b cell lymphoma , chop , doxorubicin , regimen , lymphoma , cancer research , oncology , gene knockdown , chemotherapy , biology , cell culture , cyclophosphamide , genetics
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 < .0001) but decreased etoposide‐induced cell death ( P < .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 = .026) and disease‐specific survival (68% vs 90%, P = .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.