Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

Amit Subedi; Qiang Liu; Dhanoop M. Ayyathan; David Sharon; Severine Cathelin; Mohsen Hosseini; Changjiang Xu; Veronique Voisin; Gary D. Bader; Angelo D'Alessandro; Eric R. Lechman; John E. Dick; Mark D. Minden; Jean C.Y. Wang; Steven M. Chan

doi:10.1016/j.stem.2021.06.004

Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

Amit Subedi, Qiang Liu, Dhanoop M. Ayyathan, David Sharon, Severine Cathelin, Mohsen Hosseini, Changjiang Xu, Veronique Voisin, Gary D. Bader, Angelo D'Alessandro, Eric R. Lechman, John E. Dick, Mark D. Minden, Jean C.Y. Wang, Steven M. Chan

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.

Original language	English
Pages (from-to)	1851-1867.e8
Journal	Cell Stem Cell
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.stem.2021.06.004
State	Published - 7 Oct 2021
Externally published	Yes

Bibliographical note

Funding Information:
We acknowledge support from the Princess Margaret Leukemia Tissue Bank and the patients who donated samples used in this study. This project was supported by the Acute Leukemia Translational Research Initiative from the Ontario Institute for Cancer Research. S.M.C. is generously supported by the Princess Margaret Cancer Foundation, a Leukemia Research Foundation New Investigator Award, and Canadian Institutes of Health Research (CIHR) grants PJT-159521 and PJT-175186. We also wish to thank the SPARC BioCentre at the Hospital for Sick Children and OICR Drug Discovery Program for their support with drug screening. A.S. and S.M.C. wrote the manuscript. A.S. Q.L. J.C.Y.W. and S.M.C. designed the study and analyzed results. A.S. Q.L. D.M.A. D.S. S.C. M.H. and E.R.L. performed the experiments. C.X. V.V. and G.D.B. performed the bioinformatic analysis of drug screen. A.D. performed the metabolomic analysis. M.D.M. and J.E.D. supervised research. J.C.Y.W. and S.M.C. provided funding and study supervision. All authors reviewed the manuscript. The authors declare no competing interests.

Funding Information:
We acknowledge support from the Princess Margaret Leukemia Tissue Bank and the patients who donated samples used in this study. This project was supported by the Acute Leukemia Translational Research Initiative from the Ontario Institute for Cancer Research . S.M.C. is generously supported by the Princess Margaret Cancer Foundation , a Leukemia Research Foundation New Investigator Award, and Canadian Institutes of Health Research (CIHR) grants PJT-159521 and PJT-175186 . We also wish to thank the SPARC BioCentre at the Hospital for Sick Children and OICR Drug Discovery Program for their support with drug screening.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

NAD metabolism
NAMPT
SREBP signaling
acute myeloid leukemia
dipyridamole
drug screen
fatty acid
leukemic stem cells
lipotoxicity
metabolism

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Subedi, A., Liu, Q., Ayyathan, D. M., Sharon, D., Cathelin, S., Hosseini, M., Xu, C., Voisin, V., Bader, G. D., D'Alessandro, A., Lechman, E. R., Dick, J. E., Minden, M. D., Wang, J. C. Y., & Chan, S. M. (2021). Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis. Cell Stem Cell, 28(10), 1851-1867.e8. https://doi.org/10.1016/j.stem.2021.06.004

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title = "Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis",

abstract = "Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.",

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author = "Amit Subedi and Qiang Liu and Ayyathan, {Dhanoop M.} and David Sharon and Severine Cathelin and Mohsen Hosseini and Changjiang Xu and Veronique Voisin and Bader, {Gary D.} and Angelo D'Alessandro and Lechman, {Eric R.} and Dick, {John E.} and Minden, {Mark D.} and Wang, {Jean C.Y.} and Chan, {Steven M.}",

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year = "2021",

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Subedi, A, Liu, Q, Ayyathan, DM, Sharon, D, Cathelin, S, Hosseini, M, Xu, C, Voisin, V, Bader, GD, D'Alessandro, A, Lechman, ER, Dick, JE, Minden, MD, Wang, JCY & Chan, SM 2021, 'Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis', Cell Stem Cell, vol. 28, no. 10, pp. 1851-1867.e8. https://doi.org/10.1016/j.stem.2021.06.004

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T1 - Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

AU - Subedi, Amit

AU - Liu, Qiang

AU - Ayyathan, Dhanoop M.

AU - Sharon, David

AU - Cathelin, Severine

AU - Hosseini, Mohsen

AU - Xu, Changjiang

AU - Voisin, Veronique

AU - Bader, Gary D.

AU - D'Alessandro, Angelo

AU - Lechman, Eric R.

AU - Dick, John E.

AU - Minden, Mark D.

AU - Wang, Jean C.Y.

AU - Chan, Steven M.

PY - 2021/10/7

Y1 - 2021/10/7

N2 - Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.

AB - Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.

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KW - NAMPT

KW - SREBP signaling

KW - acute myeloid leukemia

KW - dipyridamole

KW - drug screen

KW - fatty acid

KW - leukemic stem cells

KW - lipotoxicity

KW - metabolism

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JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 10

ER -

Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

Abstract

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