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.

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma / Rossi A.; Orecchioni S.; Falvo P.; Tabanelli V.; Baiardi E.; Agostinelli C.; Melle F.; Motta G.; Calleri A.; Fiori S.; Corsini C.; Casadei B.; Mazzara S.; Vitolo U.; Bertolini F.; Zinzani P.L.; Alcalay M.; Pelicci P.G.; Pileri S.; Tarella C.; Derenzini E.. - In: LEUKEMIA. - ISSN 0887-6924. - STAMPA. - 36:1(2022), pp. 197-209. [10.1038/s41375-021-01347-6]

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

Agostinelli C.;Melle F.;Casadei B.;Zinzani P. L.;Pileri S.;
2022

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.
2022
Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma / Rossi A.; Orecchioni S.; Falvo P.; Tabanelli V.; Baiardi E.; Agostinelli C.; Melle F.; Motta G.; Calleri A.; Fiori S.; Corsini C.; Casadei B.; Mazzara S.; Vitolo U.; Bertolini F.; Zinzani P.L.; Alcalay M.; Pelicci P.G.; Pileri S.; Tarella C.; Derenzini E.. - In: LEUKEMIA. - ISSN 0887-6924. - STAMPA. - 36:1(2022), pp. 197-209. [10.1038/s41375-021-01347-6]
Rossi A.; Orecchioni S.; Falvo P.; Tabanelli V.; Baiardi E.; Agostinelli C.; Melle F.; Motta G.; Calleri A.; Fiori S.; Corsini C.; Casadei B.; Mazzara S.; Vitolo U.; Bertolini F.; Zinzani P.L.; Alcalay M.; Pelicci P.G.; Pileri S.; Tarella C.; Derenzini E.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/904676
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