PMID- 34632715
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20220408
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 16
IP  - 5
DP  - 2022 Mar
TI  - Targeting mitochondrial respiration and the BCL2 family in high-grade 
      MYC-associated B-cell lymphoma.
PG  - 1132-1152
LID - 10.1002/1878-0261.13115 [doi]
AB  - Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, 
      BCL2) or a variety of gene expression signatures, have been associated with 
      disease course in diffuse large B-cell lymphoma (DLBCL), although their 
      relationships and implications for targeted therapy remain to be fully unraveled. 
      We report that MYC activity is closely correlated with-and most likely a driver 
      of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, 
      pointing to OxPhos enzymes, in particular mitochondrial electron transport chain 
      (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated 
      lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex 
      I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated 
      stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, 
      which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold 
      in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory 
      compound venetoclax synergized with IACS-010759 against double-hit lymphoma 
      (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In 
      BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by 
      the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select 
      BH3-mimetic drugs provides a novel therapeutic principle against aggressive, 
      MYC-associated DLBCL variants.
CI  - (c) 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
      behalf of Federation of European Biochemical Societies.
FAU - Donati, Giulio
AU  - Donati G
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Rava, Micol
AU  - Rava M
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Filipuzzi, Marco
AU  - Filipuzzi M
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Nicoli, Paola
AU  - Nicoli P
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Cassina, Laura
AU  - Cassina L
AD  - IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Verrecchia, Alessandro
AU  - Verrecchia A
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Doni, Mirko
AU  - Doni M
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Rodighiero, Simona
AU  - Rodighiero S
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Parodi, Federica
AU  - Parodi F
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
FAU - Boletta, Alessandra
AU  - Boletta A
AD  - IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Vellano, Christopher P
AU  - Vellano CP
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology 
      (TRACTION), Houston, TX, USA.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - Translational Research to Advance Therapeutics and Innovation in Oncology 
      (TRACTION), Houston, TX, USA.
FAU - Draetta, Giulio F
AU  - Draetta GF
AD  - Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Amati, Bruno
AU  - Amati B
AUID- ORCID: 0000-0002-2958-1799
AD  - European Institute of Oncology (IEO)-IRCCS, Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211111
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 0 (BCL2 protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Proto-Oncogene Proteins c-myc)
SB  - IM
MH  - Humans
MH  - *Lymphoma, Large B-Cell, Diffuse/drug therapy/genetics
MH  - Oncogenes
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - *Proto-Oncogene Proteins c-myc/genetics/metabolism
MH  - Respiration
PMC - PMC8895457
OTO - NOTNLM
OT  - BCL2
OT  - DLBCL
OT  - Integrated Stress Response
OT  - MYC
OT  - OxPhos
OT  - chemotherapy
COIS- The authors declare no conflict of interest.
EDAT- 2021/10/12 06:00
MHDA- 2022/04/09 06:00
PMCR- 2022/03/01
CRDT- 2021/10/11 06:40
PHST- 2021/08/27 00:00 [revised]
PHST- 2021/05/17 00:00 [received]
PHST- 2021/10/08 00:00 [accepted]
PHST- 2021/10/12 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2021/10/11 06:40 [entrez]
PHST- 2022/03/01 00:00 [pmc-release]
AID - MOL213115 [pii]
AID - 10.1002/1878-0261.13115 [doi]
PST - ppublish
SO  - Mol Oncol. 2022 Mar;16(5):1132-1152. doi: 10.1002/1878-0261.13115. Epub 2021 Nov 
      11.