Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.

Adult Aged Aged, 80 and over Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology Apoptosis / drug effects Bridged Bicyclo Compounds, Heterocyclic / pharmacology Cell Line, Tumor Clonal Evolution / drug effects Disease Progression Drug Resistance, Neoplasm / drug effects Energy Metabolism / drug effects Female Gene Expression Regulation, Neoplastic Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy Male Mice Middle Aged Mitochondria / drug effects Myeloid Cell Leukemia Sequence 1 Protein / metabolism Oxidative Phosphorylation / drug effects Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors Sulfonamides / pharmacology Treatment Outcome Xenograft Model Antitumor Assays
AMPK BCL-2 CRISPR/Cas9 chronic lymphocytic leukemia clonal evolution drug resistance genome-wide screen metabolism mitochondrion venetoclax

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
14 10 2019
Historique:
received: 27 02 2019
revised: 04 07 2019
accepted: 15 08 2019
pubmed: 24 9 2019
medline: 26 5 2020
entrez: 24 9 2019
Statut: ppublish

Résumé

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.

Identifiants

DOI: 10.1016/j.ccell.2019.08.005 PMID: 31543463 PMC: PMC6801112
pubmed: 31543463
pii: S1535-6108(19)30373-3
doi: 10.1016/j.ccell.2019.08.005
pmc: PMC6801112
mid: NIHMS1539643
pii:
doi:

Substances chimiques

BCL2 protein, human 0
Bridged Bicyclo Compounds, Heterocyclic 0
MCL1 protein, human 0
Myeloid Cell Leukemia Sequence 1 Protein 0
Proto-Oncogene Proteins c-bcl-2 0
Sulfonamides 0
venetoclax N54AIC43PW

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

369-384.e13

Subventions

Organisme : NCI NIH HHS
ID : U10 CA180861
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007627
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210986
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122455
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA216772
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA155010
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233338
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214125
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA190861
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216273
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS083524
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA206978
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213442
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM095567
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA081534
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Romain Guièze (R)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France; Université Clermont Auvergne, EA7453 CHELTER, 63000 Clermont-Ferrand, France.

Vivian M Liu (VM)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA.

Daniel Rosebrock (D)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Alexis A Jourdain (AA)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.

María Hernández-Sánchez (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Instituto de Investigación Biomédica de Salamanca, Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca, 37007 Salamanca, Spain; Servicio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain.

Aina Martinez Zurita (A)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Jing Sun (J)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Elisa Ten Hacken (E)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.

Kaitlyn Baranowski (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Philip A Thompson (PA)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Jin-Mi Heo (JM)

Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.

Zachary Cartun (Z)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Ozan Aygün (O)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

J Bryan Iorgulescu (JB)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.

Wandi Zhang (W)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Giulia Notarangelo (G)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA.

Dimitri Livitz (D)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Shuqiang Li (S)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Matthew S Davids (MS)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.

Anat Biran (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Stacey M Fernandes (SM)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Jennifer R Brown (JR)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.

Ana Lako (A)

Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Zoe B Ciantra (ZB)

Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Matthew A Lawlor (MA)

Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.

Derin B Keskin (DB)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.

Namrata D Udeshi (ND)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

William G Wierda (WG)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Kenneth J Livak (KJ)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.

Anthony G Letai (AG)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.

Donna Neuberg (D)

Harvard Medical School, Boston, MA 02215, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

J Wade Harper (JW)

Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.

Steven A Carr (SA)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Federica Piccioni (F)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Christopher J Ott (CJ)

Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.

Ignaty Leshchiner (I)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Cory M Johannessen (CM)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

John Doench (J)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Vamsi K Mootha (VK)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.

Gad Getz (G)

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.

Catherine J Wu (CJ)

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: cwu@partners.org.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Eucaryotes › Animaux › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques, cycle ponté › Composés hétérocycliques bicycliques › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Phénomènes génétiques › Évolution clonale › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-bcl-2 › Protéine Mcl-1 › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Métabolisme › Phosphorylation › Phosphorylation oxydative › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-bcl-2 › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Composés chimiques organiques › Composés du soufre › Sulfones › Sulfonamides › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Qualité, accès, évaluation des soins de santé › Qualité des soins de santé › Mécanismes d'évaluation des soins de santé › Évaluation des résultats et des processus en soins de santé › Évaluation de résultat (soins) › Résultat thérapeutique › Mitochondrial Reprogramming Underlies...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Mitochondrial Reprogramming Underlies...