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Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.
Rossi, Alessandra; Orecchioni, Stefania; Falvo, Paolo; Tabanelli, Valentina; Baiardi, Elena; Agostinelli, Claudio; Melle, Federica; Motta, Giovanna; Calleri, Angelica; Fiori, Stefano; Corsini, Chiara; Casadei, Beatrice; Mazzara, Saveria; Vitolo, Umberto; Bertolini, Francesco; Zinzani, Pier Luigi; Alcalay, Myriam; Pelicci, Pier Giuseppe; Pileri, Stefano; Tarella, Corrado; Derenzini, Enrico.
Afiliação
  • Rossi A; Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Orecchioni S; Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Falvo P; Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Tabanelli V; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Baiardi E; Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Agostinelli C; Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
  • Melle F; Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
  • Motta G; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Calleri A; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Fiori S; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Corsini C; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Casadei B; Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Mazzara S; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology and Medical Oncology "L. e A. Seragnoli", Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
  • Vitolo U; Division of diagnostic Haematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Bertolini F; Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
  • Zinzani PL; Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Alcalay M; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology and Medical Oncology "L. e A. Seragnoli", Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
  • Pelicci PG; Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Pileri S; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
  • Tarella C; Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
  • Derenzini E; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Leukemia ; 36(1): 197-209, 2022 01.
Article em En | MEDLINE | ID: mdl-34304248
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / Tiofenos / Ureia / Regulação Leucêmica da Expressão Gênica / Linfoma Difuso de Grandes Células B / Compostos Bicíclicos Heterocíclicos com Pontes / Proteínas Proto-Oncogênicas c-bcl-2 / Enzimas Reparadoras do DNA Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / Tiofenos / Ureia / Regulação Leucêmica da Expressão Gênica / Linfoma Difuso de Grandes Células B / Compostos Bicíclicos Heterocíclicos com Pontes / Proteínas Proto-Oncogênicas c-bcl-2 / Enzimas Reparadoras do DNA Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2022 Tipo de documento: Article