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

2021; Springer Nature; Volume: 36; Issue: 1 Linguagem: Inglês

10.1038/s41375-021-01347-6

1476-5551

Alessandra Rossi, Stefania Orecchioni, Paolo Falvo, Valentina Tabanelli, Elena Baiardi, Claudio Agostinelli, Federica Melle, Giovanna Motta, Angelica Calleri, Stefano Fiori, Chiara Corsini, Beatrice Casadei, Saveria Mazzara, Umberto Vitolo, Francesco Bertolini, Pier Luigi Zinzani, Myriam Alcalay, Pier Giuseppe Pelicci, Stefano Pileri, Corrado Tarella, Enrico Derenzini,

Immune Cell Function and Interaction

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.