PMID- 34304248
OWN - NLM
STAT- MEDLINE
DCOM- 20220218
LR  - 20230206
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 36
IP  - 1
DP  - 2022 Jan
TI  - Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large 
      B-cell lymphoma.
PG  - 197-209
LID - 10.1038/s41375-021-01347-6 [doi]
AB  - 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.
CI  - (c) 2021. The Author(s).
FAU - Rossi, Alessandra
AU  - Rossi A
AD  - Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy.
FAU - Orecchioni, Stefania
AU  - Orecchioni S
AD  - Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
FAU - Falvo, Paolo
AU  - Falvo P
AD  - Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
FAU - Tabanelli, Valentina
AU  - Tabanelli V
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Baiardi, Elena
AU  - Baiardi E
AUID- ORCID: 0000-0002-5432-4751
AD  - Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy.
FAU - Agostinelli, Claudio
AU  - Agostinelli C
AD  - Hematopathology Unit, Department of Experimental, Diagnostic, and Specialty 
      Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
AD  - Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 
      Bologna, Italy.
FAU - Melle, Federica
AU  - Melle F
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Motta, Giovanna
AU  - Motta G
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Calleri, Angelica
AU  - Calleri A
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Fiori, Stefano
AU  - Fiori S
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Corsini, Chiara
AU  - Corsini C
AD  - Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
FAU - Casadei, Beatrice
AU  - Casadei B
AD  - 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.
FAU - Mazzara, Saveria
AU  - Mazzara S
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Vitolo, Umberto
AU  - Vitolo U
AUID- ORCID: 0000-0001-7772-2747
AD  - Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, 
      FPO-IRCCS, Candiolo, Italy.
FAU - Bertolini, Francesco
AU  - Bertolini F
AD  - Laboratory of Hematology-Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
FAU - Zinzani, Pier Luigi
AU  - Zinzani PL
AUID- ORCID: 0000-0002-2112-2651
AD  - 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.
FAU - Alcalay, Myriam
AU  - Alcalay M
AD  - Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
AD  - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
FAU - Pelicci, Pier Giuseppe
AU  - Pelicci PG
AD  - Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 
      Milan, Italy.
AD  - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
FAU - Pileri, Stefano
AU  - Pileri S
AD  - Division of diagnostic Haematopathology, IEO European Institute of Oncology 
      IRCCS, Milan, Italy.
FAU - Tarella, Corrado
AU  - Tarella C
AUID- ORCID: 0000-0003-1473-6046
AD  - Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy. 
      corrado.tarella@unimi.it.
AD  - Department of Health Sciences, University of Milan, Milan, Italy. 
      corrado.tarella@unimi.it.
FAU - Derenzini, Enrico
AU  - Derenzini E
AUID- ORCID: 0000-0002-7154-8140
AD  - Onco-Hematology Division, IEO European Institute of Oncology IRCCS, Milan, Italy. 
      enrico.derenzini@ieo.it.
AD  - Department of Health Sciences, University of Milan, Milan, Italy. 
      enrico.derenzini@ieo.it.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210724
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BCL2 protein, human)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Sulfonamides)
RN  - 0 (Thiophenes)
RN  - 8W8T17847W (Urea)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
RN  - N54AIC43PW (venetoclax)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/pharmacology
MH  - Biomarkers, Tumor/genetics/metabolism
MH  - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology
MH  - DNA Repair Enzymes/*antagonists & inhibitors
MH  - Drug Therapy, Combination
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Expression Regulation, Leukemic/*drug effects
MH  - Humans
MH  - Lymphoma, Large B-Cell, Diffuse/*drug therapy/metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - Prognosis
MH  - Prospective Studies
MH  - Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors
MH  - Retrospective Studies
MH  - Sulfonamides/*pharmacology
MH  - Survival Rate
MH  - Thiophenes/*pharmacology
MH  - Urea/*analogs & derivatives/pharmacology
MH  - Young Adult
PMC - PMC8727301
COIS- AR, SO, PF, VT, EB, CA, FM, GM, AC, SF, CC, BC, SM, MA: nothing to disclose; UV: 
      Consulting or advisory role for Celgene, Janssen, Genmab, Incyte, Bristol-Myers 
      Squibb; speakers' bureau with Roche, Celgene, Janssen, Gilead Sciences, Sandoz, 
      Abbvie; research funding from Roche and Celgene; research funding from Roche and 
      Celgene. FB: research funding, Gilead Sciences, Menarini, Emercell. PLZ: 
      speakers' bureau or advisory boards for Verastem, Celltrion, Gilead, 
      Janssen-cilag, Bristol-Myers Squibb, Servier, Sandoz, MSD, Immune Design, 
      Celgene, Portola, Roche, Eusapharma, Kyowa Kirin, Sanofi. PGP: member of advisory 
      commette BRIC Copenaghen, MD Anderson Cancer Center, Houston (Tx). SP: Advisory 
      Boards for Celgene, NanoString, Roche. CT: advisory board, ADC- Therapeutics. ED: 
      research funding from TG-Therapeutics, ADC-Therapeutics, Takeda; Advisory board 
      for Gilead, Astra Zeneca, Takeda.
EDAT- 2021/07/26 06:00
MHDA- 2022/02/19 06:00
PMCR- 2021/07/24
CRDT- 2021/07/25 20:49
PHST- 2020/11/01 00:00 [received]
PHST- 2021/07/08 00:00 [accepted]
PHST- 2021/06/28 00:00 [revised]
PHST- 2021/07/26 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/07/25 20:49 [entrez]
PHST- 2021/07/24 00:00 [pmc-release]
AID - 10.1038/s41375-021-01347-6 [pii]
AID - 1347 [pii]
AID - 10.1038/s41375-021-01347-6 [doi]
PST - ppublish
SO  - Leukemia. 2022 Jan;36(1):197-209. doi: 10.1038/s41375-021-01347-6. Epub 2021 Jul 
      24.