ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Mark A. Gregory; Angelo D'Alessandro; Francesca Alvarez-Calderon; Jihye Kim; Travis Nemkov; Biniam Adane; Andrii I. Rozhok; Amit Kumar; Vijay Kumar; Daniel A. Pollyea; Michael F. Wempe; Craig T. Jordan; Natalie J. Serkova; Aik Choon Tan; Kirk C. Hansen; James DeGregori

doi:10.1073/pnas.1603876113

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Mark A. Gregory, Angelo D'Alessandro, Francesca Alvarez-Calderon, Jihye Kim, Travis Nemkov, Biniam Adane, Andrii I. Rozhok, Amit Kumar, Vijay Kumar, Daniel A. Pollyea, Michael F. Wempe, Craig T. Jordan, Natalie J. Serkova, Aik Choon Tan, Kirk C. Hansen, James DeGregori

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

79 Citations (Scopus)

Abstract

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy.We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

Original language	English
Pages (from-to)	E6669-E6678
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	43
DOIs	https://doi.org/10.1073/pnas.1603876113
Publication status	Published - 2016 Oct 25

Bibliographical note

Funding Information:
We thank Vadym Zaberezhnyy, Andrea Merz, and Dr. Chris Porter for assistance with experiments. We thank Karen Helm, Christine Childs, and Lester Acosta of the University of Colorado Cancer Center Flow Cytometry Core (supported by NIH Grant P30-CA46934) for technical assistance. Grants from the National Institutes of Health (K22-CA133182 to M.A.G. and F31-CA157166 to F.A.C.), the Cancer League of Colorado (to M.A.G.), and the Leukemia Lymphoma Society (to J.D.) supported these studies. The research used services of the Medicinal Chemistry Core Facility, which is supported in part by NIH/National Center for Advancing Translational Sciences Grant UL1TR001082 to Colorado Clinical & Translational Sciences Institute.

Keywords

ATM
Acute myeloid leukemia
FLT3
Glutathione
Metabolism

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.1603876113

Cite this

Gregory, M. A., D'Alessandro, A., Alvarez-Calderon, F., Kim, J., Nemkov, T., Adane, B., Rozhok, A. I., Kumar, A., Kumar, V., Pollyea, D. A., Wempe, M. F., Jordan, C. T., Serkova, N. J., Tan, A. C., Hansen, K. C., & DeGregori, J. (2016). ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 113(43), E6669-E6678. https://doi.org/10.1073/pnas.1603876113

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. / Gregory, Mark A.; D'Alessandro, Angelo; Alvarez-Calderon, Francesca et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 43, 25.10.2016, p. E6669-E6678.

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

Gregory, MA, D'Alessandro, A, Alvarez-Calderon, F, Kim, J, Nemkov, T, Adane, B, Rozhok, AI, Kumar, A, Kumar, V, Pollyea, DA, Wempe, MF, Jordan, CT, Serkova, NJ, Tan, AC, Hansen, KC & DeGregori, J 2016, 'ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 43, pp. E6669-E6678. https://doi.org/10.1073/pnas.1603876113

@article{63e9bcafbd274ebbaed5d13ca64800e3,

title = "ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia",

abstract = "Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy.We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.",

keywords = "ATM, Acute myeloid leukemia, FLT3, Glutathione, Metabolism",

author = "Gregory, {Mark A.} and Angelo D'Alessandro and Francesca Alvarez-Calderon and Jihye Kim and Travis Nemkov and Biniam Adane and Rozhok, {Andrii I.} and Amit Kumar and Vijay Kumar and Pollyea, {Daniel A.} and Wempe, {Michael F.} and Jordan, {Craig T.} and Serkova, {Natalie J.} and Tan, {Aik Choon} and Hansen, {Kirk C.} and James DeGregori",

note = "Funding Information: We thank Vadym Zaberezhnyy, Andrea Merz, and Dr. Chris Porter for assistance with experiments. We thank Karen Helm, Christine Childs, and Lester Acosta of the University of Colorado Cancer Center Flow Cytometry Core (supported by NIH Grant P30-CA46934) for technical assistance. Grants from the National Institutes of Health (K22-CA133182 to M.A.G. and F31-CA157166 to F.A.C.), the Cancer League of Colorado (to M.A.G.), and the Leukemia Lymphoma Society (to J.D.) supported these studies. The research used services of the Medicinal Chemistry Core Facility, which is supported in part by NIH/National Center for Advancing Translational Sciences Grant UL1TR001082 to Colorado Clinical & Translational Sciences Institute.",

year = "2016",

month = oct,

day = "25",

doi = "10.1073/pnas.1603876113",

language = "English",

volume = "113",

pages = "E6669--E6678",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "43",

}

TY - JOUR

T1 - ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

AU - Gregory, Mark A.

AU - D'Alessandro, Angelo

AU - Alvarez-Calderon, Francesca

AU - Kim, Jihye

AU - Nemkov, Travis

AU - Adane, Biniam

AU - Rozhok, Andrii I.

AU - Kumar, Amit

AU - Kumar, Vijay

AU - Pollyea, Daniel A.

AU - Wempe, Michael F.

AU - Jordan, Craig T.

AU - Serkova, Natalie J.

AU - Tan, Aik Choon

AU - Hansen, Kirk C.

AU - DeGregori, James

N1 - Funding Information: We thank Vadym Zaberezhnyy, Andrea Merz, and Dr. Chris Porter for assistance with experiments. We thank Karen Helm, Christine Childs, and Lester Acosta of the University of Colorado Cancer Center Flow Cytometry Core (supported by NIH Grant P30-CA46934) for technical assistance. Grants from the National Institutes of Health (K22-CA133182 to M.A.G. and F31-CA157166 to F.A.C.), the Cancer League of Colorado (to M.A.G.), and the Leukemia Lymphoma Society (to J.D.) supported these studies. The research used services of the Medicinal Chemistry Core Facility, which is supported in part by NIH/National Center for Advancing Translational Sciences Grant UL1TR001082 to Colorado Clinical & Translational Sciences Institute.

PY - 2016/10/25

Y1 - 2016/10/25

N2 - Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy.We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

AB - Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy.We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

KW - ATM

KW - Acute myeloid leukemia

KW - FLT3

KW - Glutathione

KW - Metabolism

UR - http://www.scopus.com/inward/record.url?scp=84992315972&partnerID=8YFLogxK

U2 - 10.1073/pnas.1603876113

DO - 10.1073/pnas.1603876113

M3 - Article

C2 - 27791036

AN - SCOPUS:84992315972

SN - 0027-8424

VL - 113

SP - E6669-E6678

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 43

ER -

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this