Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

Alicia Cole; Zezhou Wang; Etienne Coyaud; Veronique Voisin; Marcela Gronda; Yulia Jitkova; Rachel Mattson; Rose Hurren; Sonja Babovic; Neil Maclean; Ian Restall; Xiaoming Wang; Danny V. Jeyaraju; Mahadeo A. Sukhai; Swayam Prabha; Shaheena Bashir; Ashwin Ramakrishnan; Elisa Leung; Yi Hua Qia; Nianxian Zhang; Kevin R. Combes; Troy Ketela; Fengshu Lin; Walid A. Houry; Ahmed Aman; Rima Al-awar; Wei Zheng; Erno Wienholds; Chang Jiang Xu; John Dick; Jean C.Y. Wang; Jason Moffat; Mark D. Minden; Connie J. Eaves; Gary D. Bader; Zhenyue Hao; Steven M. Kornblau; Brian Raught; Aaron D. Schimmer

doi:10.1016/j.ccell.2015.05.004

Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

Alicia Cole, Zezhou Wang, Etienne Coyaud, Veronique Voisin, Marcela Gronda, Yulia Jitkova, Rachel Mattson, Rose Hurren, Sonja Babovic, Neil Maclean, Ian Restall, Xiaoming Wang, Danny V. Jeyaraju, Mahadeo A. Sukhai, Swayam Prabha, Shaheena Bashir, Ashwin Ramakrishnan, Elisa Leung, Yi Hua Qia, Nianxian ZhangKevin R. Combes, Troy Ketela, Fengshu Lin, Walid A. Houry, Ahmed Aman, Rima Al-awar, Wei Zheng, Erno Wienholds, Chang Jiang Xu, John Dick, Jean C.Y. Wang, Jason Moffat, Mark D. Minden, Connie J. Eaves, Gary D. Bader, Zhenyue Hao, Steven M. Kornblau, Brian Raught, Aaron D. Schimmer

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

235 Scopus citations

Abstract

From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

Original language	English (US)
Pages (from-to)	864-876
Number of pages	13
Journal	Cancer Cell
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2015.05.004
State	Published - Jun 8 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.05.004

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Cole, A., Wang, Z., Coyaud, E., Voisin, V., Gronda, M., Jitkova, Y., Mattson, R., Hurren, R., Babovic, S., Maclean, N., Restall, I., Wang, X., Jeyaraju, D. V., Sukhai, M. A., Prabha, S., Bashir, S., Ramakrishnan, A., Leung, E., Qia, Y. H., ... Schimmer, A. D. (2015). Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer Cell, 27(6), 864-876. https://doi.org/10.1016/j.ccell.2015.05.004

Cole, A, Wang, Z, Coyaud, E, Voisin, V, Gronda, M, Jitkova, Y, Mattson, R, Hurren, R, Babovic, S, Maclean, N, Restall, I, Wang, X, Jeyaraju, DV, Sukhai, MA, Prabha, S, Bashir, S, Ramakrishnan, A, Leung, E, Qia, YH, Zhang, N, Combes, KR, Ketela, T, Lin, F, Houry, WA, Aman, A, Al-awar, R, Zheng, W, Wienholds, E, Xu, CJ, Dick, J, Wang, JCY, Moffat, J, Minden, MD, Eaves, CJ, Bader, GD, Hao, Z, Kornblau, SM, Raught, B & Schimmer, AD 2015, 'Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia', Cancer Cell, vol. 27, no. 6, pp. 864-876. https://doi.org/10.1016/j.ccell.2015.05.004

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title = "Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia",

abstract = "From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.",

author = "Alicia Cole and Zezhou Wang and Etienne Coyaud and Veronique Voisin and Marcela Gronda and Yulia Jitkova and Rachel Mattson and Rose Hurren and Sonja Babovic and Neil Maclean and Ian Restall and Xiaoming Wang and Jeyaraju, {Danny V.} and Sukhai, {Mahadeo A.} and Swayam Prabha and Shaheena Bashir and Ashwin Ramakrishnan and Elisa Leung and Qia, {Yi Hua} and Nianxian Zhang and Combes, {Kevin R.} and Troy Ketela and Fengshu Lin and Houry, {Walid A.} and Ahmed Aman and Rima Al-awar and Wei Zheng and Erno Wienholds and Xu, {Chang Jiang} and John Dick and Wang, {Jean C.Y.} and Jason Moffat and Minden, {Mark D.} and Eaves, {Connie J.} and Bader, {Gary D.} and Zhenyue Hao and Kornblau, {Steven M.} and Brian Raught and Schimmer, {Aaron D.}",

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year = "2015",

month = jun,

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doi = "10.1016/j.ccell.2015.05.004",

language = "English (US)",

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T1 - Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

AU - Cole, Alicia

AU - Wang, Zezhou

AU - Coyaud, Etienne

AU - Voisin, Veronique

AU - Gronda, Marcela

AU - Jitkova, Yulia

AU - Mattson, Rachel

AU - Hurren, Rose

AU - Babovic, Sonja

AU - Maclean, Neil

AU - Restall, Ian

AU - Wang, Xiaoming

AU - Jeyaraju, Danny V.

AU - Sukhai, Mahadeo A.

AU - Prabha, Swayam

AU - Bashir, Shaheena

AU - Ramakrishnan, Ashwin

AU - Leung, Elisa

AU - Qia, Yi Hua

AU - Zhang, Nianxian

AU - Combes, Kevin R.

AU - Ketela, Troy

AU - Lin, Fengshu

AU - Houry, Walid A.

AU - Aman, Ahmed

AU - Al-awar, Rima

AU - Zheng, Wei

AU - Wienholds, Erno

AU - Xu, Chang Jiang

AU - Dick, John

AU - Wang, Jean C.Y.

AU - Moffat, Jason

AU - Minden, Mark D.

AU - Eaves, Connie J.

AU - Bader, Gary D.

AU - Hao, Zhenyue

AU - Kornblau, Steven M.

AU - Raught, Brian

AU - Schimmer, Aaron D.

PY - 2015/6/8

Y1 - 2015/6/8

N2 - From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

AB - From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

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Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

Abstract

ASJC Scopus subject areas

UN SDGs

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