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Cell Metab. 2019 May 7;29(5):1217-1231.e7. doi: 10.1016/j.cmet.2019.01.011. Epub 2019 Feb 14.

Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity.

Author information

1
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
2
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
3
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
4
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
5
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
6
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
7
Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, NC, USA.
8
Department of Pathology, Duke University Medical Center, Durham, NC, USA.
9
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Electronic address: kris.wood@duke.edu.

Abstract

Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival. In particular, our analysis singled out heme biosynthesis as an unappreciated apoptosis-modifying pathway. Although heme is broadly incorporated into the proteome, reduction of heme biosynthesis potentiates apoptosis through the loss of ETC activity, resulting in baseline depolarization of the mitochondrial membrane and an increased propensity to undergo apoptosis. Collectively, our findings chart the first apoptotic map of metabolism, motivating the design of metabolically engaged combination chemotherapies and nominating heme biosynthesis as an apoptotic modulator in AML.

KEYWORDS:

CRISPR; acute myeloid leukemia; apoptosis; cancer metabolism; genetic screens; heme biosynthesis; mitochondria

PMID:
30773463
PMCID:
PMC6506362
[Available on 2020-05-07]
DOI:
10.1016/j.cmet.2019.01.011

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