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Letters to the Editor
The significance of gradient expression of chromosome region maintenance protein 1 in large cell lymphoma
Tumor cells depend on nuclear export of macromole- cules to sustain their survival.1 Chromosome region maintenance protein1 (CRM1), encoded by the XPO1 gene, is the principle receptor mediating the nuclear efflux of proteins.1 CRM1 (XPO1) is overexpressed in tumor cells to facilitate the increased demand for nuclear export of tumor suppressor proteins, leading to enhanced cell survival.1-3 The intensity of CRM1 expression has an independent prognostic value in several solid tumors and in acute myeloid leukemia where high-expression was associated with an inferior survival.2,4 Studies evaluating the presence and degree of CRM1 expression in diffuse large B-cell lymphoma (DLBCL) with respect to prognosis are limited. This topic is important given the recent approval of selinexor, a first-in-class small molecule inhibitor of CRM1, for the treatment of relapsed and/or refractory (R/R) DLBCL without the requirement to demonstrate tumor CRM1 expression.5 Therefore, we assessed the gradient expression of CRM1 in DLBCL with respect to outcomes in patients treated with anti- CD20 antibody based chemoimmunotherapy.
The study was conducted in accordance with the Declaration of Helsinki following Institutional Review Board approval at Mayo Clinic, Rochester, MN. Patients with DLBCL, primary mediastinal (thymic) large B-cell lymphoma and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements from the Molecular Epidemiology Resource (MER) cohort at the Mayo Clinic and the University of Iowa were eligible. Paraffin embedded tumor tissue obtained prior to the initiation of treatment from patients who were subsequently treated with chemoimmunotherapy was assessed for CRM1 expression through immunohisto- chemistry (IHC) on a tissue microarray (TMA) by using a CRM1 monoclonal antibody. Standard slide preparation from paraffin blocks was performed and staining was done in the following order: i) CRM1 (Cell Signaling, cat- alog-no: 46249, dilution 1:100), ii) MACH 3TM Rabbit Probe HRP Polymer Kit (Biocare Medical, Walnut Creek, CA), iii) R-Polymer HRP: MACH 3TM Rabbit Probe HRP Polymer Kit (Biocare Medical, Walnut Creek, CA, USA), iv) Chromogen: DAB+ (DakoCytomation, Carpinteria, CA, USA), v) two 5-minute incubations with water rinse. Hemotoxylin was used as the counter stain. CRM1 expression by tumor cells was graded based on compar- ing tumor cell CRM1 staining to background, non-malig-
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Figure 1. Distribution of the scores of histopathology grading of CRM1 expression on tumor tissue and the prognosis of patients with large-cell lymphoma based on CRM1 protein expression on primary tumor cells. (A) Spectrum of chromosome region maintenance protein1(CRM1) expression on tumor tissue assessed via immunohistochemistry; (B) histogram showing the distribution of the mean expression scores of CRM1, median score for the entire population was 2.5 (vertical red dashed line); ©event-free survival based on high and low CRM1 expression; (D) overall survival based on high and low CRM1 expression.
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