AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

Shanshan Pei; Mohammad Minhajuddin; Biniam Adane; Nabilah Khan; Brett M. Stevens; Stephen C. Mack; Sisi Lai; Jeremy N. Rich; Anagha Inguva; Kevin M. Shannon; Hyunmin Kim; Aik Choon Tan; Jason R. Myers; John M. Ashton; Tobias Neff; Daniel A. Pollyea; Clayton A. Smith; Craig T. Jordan

doi:10.1016/j.stem.2018.05.021

AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

Shanshan Pei, Mohammad Minhajuddin, Biniam Adane, Nabilah Khan, Brett M. Stevens, Stephen C. Mack, Sisi Lai, Jeremy N. Rich, Anagha Inguva, Kevin M. Shannon, Hyunmin Kim, Aik Choon Tan, Jason R. Myers, John M. Ashton, Tobias Neff, Daniel A. Pollyea, Clayton A. Smith, Craig T. Jordan

Department of Computer Science and Engineering

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

163 Citations (Scopus)

Abstract

Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.

Original language	English
Pages (from-to)	86-100.e6
Journal	Cell Stem Cell
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2018.05.021
Publication status	Published - 2018 Jul 5

Bibliographical note

Funding Information:
We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1 . B.A. was supported by NIH F31CA196330-01 . D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program . K.M.S. is supported by NIH R01CA193994 . A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934 , Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497 . We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082 ) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript.

Funding Information:
We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1. B.A. was supported by NIH F31CA196330-01. D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program. K.M.S. is supported by NIH R01CA193994. A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934, Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497. We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript.

Keywords

AMPK
FIS1
GSK3
acute myeloid leukemia
differentiation
leukemia stem cells
mitochondrial dynamics
mitophagy

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2018.05.021

Cite this

Pei, S., Minhajuddin, M., Adane, B., Khan, N., Stevens, B. M., Mack, S. C., Lai, S., Rich, J. N., Inguva, A., Shannon, K. M., Kim, H., Tan, A. C., Myers, J. R., Ashton, J. M., Neff, T., Pollyea, D. A., Smith, C. A., & Jordan, C. T. (2018). AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells. Cell Stem Cell, 23(1), 86-100.e6. https://doi.org/10.1016/j.stem.2018.05.021

Pei, S, Minhajuddin, M, Adane, B, Khan, N, Stevens, BM, Mack, SC, Lai, S, Rich, JN, Inguva, A, Shannon, KM, Kim, H, Tan, AC, Myers, JR, Ashton, JM, Neff, T, Pollyea, DA, Smith, CA & Jordan, CT 2018, 'AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells', Cell Stem Cell, vol. 23, no. 1, pp. 86-100.e6. https://doi.org/10.1016/j.stem.2018.05.021

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title = "AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells",

abstract = "Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.",

keywords = "AMPK, FIS1, GSK3, acute myeloid leukemia, differentiation, leukemia stem cells, mitochondrial dynamics, mitophagy",

author = "Shanshan Pei and Mohammad Minhajuddin and Biniam Adane and Nabilah Khan and Stevens, {Brett M.} and Mack, {Stephen C.} and Sisi Lai and Rich, {Jeremy N.} and Anagha Inguva and Shannon, {Kevin M.} and Hyunmin Kim and Tan, {Aik Choon} and Myers, {Jason R.} and Ashton, {John M.} and Tobias Neff and Pollyea, {Daniel A.} and Smith, {Clayton A.} and Jordan, {Craig T.}",

note = "Funding Information: We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1 . B.A. was supported by NIH F31CA196330-01 . D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program . K.M.S. is supported by NIH R01CA193994 . A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934 , Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497 . We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082 ) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript. Funding Information: We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1. B.A. was supported by NIH F31CA196330-01. D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program. K.M.S. is supported by NIH R01CA193994. A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934, Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497. We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript.",

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AU - Pei, Shanshan

AU - Minhajuddin, Mohammad

AU - Adane, Biniam

AU - Khan, Nabilah

AU - Stevens, Brett M.

AU - Mack, Stephen C.

AU - Lai, Sisi

AU - Rich, Jeremy N.

AU - Inguva, Anagha

AU - Shannon, Kevin M.

AU - Kim, Hyunmin

AU - Tan, Aik Choon

AU - Myers, Jason R.

AU - Ashton, John M.

AU - Neff, Tobias

AU - Pollyea, Daniel A.

AU - Smith, Clayton A.

AU - Jordan, Craig T.

N1 - Funding Information: We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1 . B.A. was supported by NIH F31CA196330-01 . D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program . K.M.S. is supported by NIH R01CA193994 . A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934 , Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497 . We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082 ) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript. Funding Information: We gratefully acknowledge our patients and their families for their participation in this study. C.T.J. is generously supported by the Nancy Carroll Allen Chair in Hematology Research and NIH grants R01CA200707 and R01CA166265-05S1. B.A. was supported by NIH F31CA196330-01. D.A.P. is supported by the University of Colorado Department of Medicine Outstanding Early Career Scholar Program. K.M.S. is supported by NIH R01CA193994. A.C.T. is supported by University of Colorado Cancer Center support grant P30CA046934, Bioinformatics Core. A.I. is supported by NIH MSTP T32 GM008497. We are also grateful for funding from the University of Colorado Cancer Center Development Therapeutics Pilot Grant Award. We thank the Genomic Center at University of Rochester Medical Campus for their support with RNA-seq data analysis. We thank the Electron Microscopy Service core at University of Colorado-Boulder for their critical support with TEM. We also thank the Advanced Light Microscopy Core at the University of Colorado-Anschutz Medical Campus (supported in part by NIH/NCATS Colorado CTSI grant UL1 TR001082) for their help with confocal studies. We greatly appreciate Drs. James DeGregori and Eric Pietras for their comments on our manuscript.

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N2 - Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.

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KW - FIS1

KW - GSK3

KW - acute myeloid leukemia

KW - differentiation

KW - leukemia stem cells

KW - mitochondrial dynamics

KW - mitophagy

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AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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