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Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

ABSTRACT: Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.

SUBMITTER: Rossi A

PROVIDER: S-EPMC8727301 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

Rossi Alessandra A Orecchioni Stefania S Falvo Paolo P Tabanelli Valentina V Baiardi Elena E Agostinelli Claudio C Melle Federica F Motta Giovanna G Calleri Angelica A Fiori Stefano S Corsini Chiara C Casadei Beatrice B Mazzara Saveria S Vitolo Umberto U Bertolini Francesco F Zinzani Pier Luigi PL Alcalay Myriam M Pelicci Pier Giuseppe PG Pileri Stefano S Tarella Corrado C Derenzini Enrico E

Leukemia 20210724 1

Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicati ...[more]

PMID: 34304248

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Project description:Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in adults, whose prognostic scoring system remains to be improved. Dysfunction of DNA repair genes is closely associated with the development and prognosis of diffuse large B-cell lymphoma. The aim of this study was to establish and validate a DNA repair-related gene signature associated with the prognosis of DLBCL and to investigate the clinical predictive value of this signature. Methods DLBCL cases were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. One hundred ninety-nine DNA repair-related gene sets were retrieved from the GeneCards database. The LASSO Cox regression was used to generate the DNA repair-related gene signature. Subsequently, the level of immune cell infiltration and the correlation between the gene signature and immune cells were analyzed using the CIBERSORT algorithm. Based on the Genomics of Drug Sensitivity in Cancer (GDSC) database, the relationship between the signature and drug sensitivity was analyzed, and together with the nomogram and gene set variation analysis (GSVA), the value of the signature for clinical application was evaluated. Results A total of 14 DNA repair genes were screened out and included in the final risk model. Subgroup analysis of the training and validation cohorts showed that the risk model accurately predicted overall survival of DLBCL patients, with patients in the high-risk group having a worse prognosis than patients in the low-risk group. Subsequently, the risk score was confirmed as an independent prognostic factor by multivariate analysis. Furthermore, by CIBERSORT analysis, we discovered that immune cells, such as regulatory T cells (Tregs), activated memory CD4+ T cells, and gamma delta T cells showed significant differences between the high- and low-risk groups. In addition, we found some interesting associations of our signature with immune checkpoint genes (CD96, TGFBR1, and TIGIT). By analyzing drug sensitivity data in the GDSC database, we were able to identify potential therapeutics for DLBCL patients stratified according to our signature. Conclusions Our study identified and validated a 14-DNA repair-related gene signature for stratification and prognostic prediction of DLBCL patients, which might guide clinical personalization of treatment.

Dataset Information

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

Publications

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

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