Extranucleolar CYCLON Staining Pattern Is Strongly Associated to Relapse/Refractory Disease in R-CHOP-treated DLBCL.
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ABSTRACT:
SUBMITTER: Bouroumeau A
PROVIDER: S-EPMC8196088 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30-40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.
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Project description:Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in ~?5% of patients treated with R-CHOP. We hypothesized that adding lenalidomide to R-CHOP (R2CHOP) may decrease the risk of CNS relapse. We analyzed records for patients with DLBCL from two R2CHOP trials. We assessed variables pertinent to the CNS-International Prognostic Index (CNS-IPI) scoring system and classified patients into groups of low, intermediate, and high risk of CNS relapse. The 2-year CNS relapse rate for each risk group was estimated using the Kaplan-Meier method and compared with reported rates in cohorts treated with contemporary chemoimmunotherapy. A total of 136 patients were included. Mean age was 65 and median follow-up was 48.2 months. 10.3, 71.3, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed CNS relapse, corresponding to an incidence of 0.7% and an estimated 2-year CNS relapse rate of 0.9% for the entire R2CHOP cohort. The estimated 2-year CNS relapse rates for the low, intermediate, and high-risk groups were 0, 0, and 5.0%, respectively. Frontline therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of CNS relapse.
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Project description:Current understanding of the mutation spectrum of relapsed/refractory (RR) tumors is limited. We performed whole exome sequencing (WES) on 47 diffuse large B cell lymphoma (DLBCL) tumors that persisted after R-CHOP treatment, 8 matched to primary biopsies. We compared genomic alterations from the RR cohort against two treatment-naïve DLBCL cohorts (n=112). While the overall number and types of mutations did not differ significantly, we identified frequency changes in DLBCL driver genes. The overall frequency of MYD88 mutant samples increased (12% to 19%), but we noted a decrease in p.L265P (8% to 4%) and increase in p.S219C mutations (2% to 6%). CARD11 p.D230N, PIM1 p.K115N and CD79B p.Y196C mutations were not observed in the RR cohort, although these mutations were prominent in the primary DLBCL samples. We observed an increase in BCL2 mutations (21% to 38% of samples), BCL2 amplifications (3% to 6% of samples) and CREBBP mutations (31% to 42% of samples) in the RR cohort, supported by acquisition of mutations in these genes in relapsed compared to diagnostic biopsies from the same patient. These increases may reflect the genetic characteristics of R-CHOP RR tumors expected to be enriched for during clinical trial enrollment. These findings hold significance for a number of emerging targeted therapies aligned to genetic targets and biomarkers in DLBCL, reinforcing the importance of time-of-treatment biomarker screening during DLBCL therapy selection.
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Project description:TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies.
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Project description:Diffuse large B-cell lymphoma (DLBCL) is the most frequent entity among non-Hodgkin lymphoma (NHL). It is a clinically and biologically heterogeneous disease regarding treatment response and long-term outcome. The anthracycline-based regimen R-CHOP is still considered as the standard of care for first-line treatment allowing achieving a complete response for approximately 60% of the patients. The prognosis of patients with primary refractory or relapsed (R/R) disease is particularly poor with a median overall survival below one year. Only a fraction of R/R patients can be cured with salvage therapies due to the acquisition of chemoresistance. We conducted a large-scale and deep proteomic investigation of the proteome profiles of R/R DLBCL patients compared to chemosensitive patients in order to identify new potential biomarkers related to resistance to treatment and to better understand the biological mechanisms underlying chemoresistance.
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