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Cancer Cell. 2019 Oct 14;36(4):369-384.e13. doi: 10.1016/j.ccell.2019.08.005. Epub 2019 Sep 19.

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

Author information

1
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.
2
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.
3
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4
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.
5
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.
6
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.
7
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.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.
9
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
10
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
11
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.
12
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.
13
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.
14
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
15
Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.
16
Harvard Medical School, Boston, MA 02215, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
17
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.
18
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.

Abstract

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.

KEYWORDS:

AMPK; BCL-2; CRISPR/Cas9; chronic lymphocytic leukemia; clonal evolution; drug resistance; genome-wide screen; metabolism; mitochondrion; venetoclax

PMID:
31543463
PMCID:
PMC6801112
[Available on 2020-10-14]
DOI:
10.1016/j.ccell.2019.08.005

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