IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30223-9.html
   My bibliography  Save this article

Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

Author

Listed:
  • Mahmoud A. Bassal

    (Harvard Medical School
    National University of Singapore)

  • Saumya E. Samaraweera

    (University of South Australia and SA Pathology)

  • Kelly Lim

    (University of Adelaide)

  • Brooks A. Benard

    (Stanford University)

  • Sheree Bailey

    (University of South Australia)

  • Satinder Kaur

    (University of Adelaide)

  • Paul Leo

    (Translational Research Institute)

  • John Toubia

    (University of South Australia and SA Pathology)

  • Chloe Thompson-Peach

    (University of Adelaide)

  • Tran Nguyen

    (University of South Australia and SA Pathology)

  • Kyaw Ze Ya Maung

    (University of South Australia and SA Pathology)

  • Debora A. Casolari

    (University of South Australia and SA Pathology)

  • Diana G. Iarossi

    (University of South Australia and SA Pathology)

  • Ilaria S. Pagani

    (South Australian Health and Medical Research Institute)

  • Jason Powell

    (University of South Australia and SA Pathology)

  • Stuart Pitson

    (University of South Australia and SA Pathology)

  • Siria Natera

    (The University of Melbourne)

  • Ute Roessner

    (The University of Melbourne)

  • Ian D. Lewis

    (Adelaide Oncology & Haematology)

  • Anna L. Brown

    (University of South Australia and SA Pathology
    University of South Australia
    SA Pathology)

  • Daniel G. Tenen

    (Harvard Medical School
    National University of Singapore)

  • Nirmal Robinson

    (University of South Australia and SA Pathology)

  • David M. Ross

    (University of South Australia and SA Pathology
    University of Adelaide
    South Australian Health and Medical Research Institute
    Royal Adelaide Hospital)

  • Ravindra Majeti

    (Stanford University)

  • Thomas J. Gonda

    (University of South Australia
    University of Queensland)

  • Daniel Thomas

    (University of Adelaide
    Stanford University
    South Australian Health and Medical Research Institute)

  • Richard J. D’Andrea

    (University of South Australia and SA Pathology)

Abstract

The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.

Suggested Citation

  • Mahmoud A. Bassal & Saumya E. Samaraweera & Kelly Lim & Brooks A. Benard & Sheree Bailey & Satinder Kaur & Paul Leo & John Toubia & Chloe Thompson-Peach & Tran Nguyen & Kyaw Ze Ya Maung & Debora A. Ca, 2022. "Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30223-9
    DOI: 10.1038/s41467-022-30223-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30223-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-30223-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Jaekyoung Son & Costas A. Lyssiotis & Haoqiang Ying & Xiaoxu Wang & Sujun Hua & Matteo Ligorio & Rushika M. Perera & Cristina R. Ferrone & Edouard Mullarky & Ng Shyh-Chang & Ya’an Kang & Jason B. Flem, 2013. "Correction: Corrigendum: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway," Nature, Nature, vol. 499(7459), pages 504-504, July.
    3. Yaara Oren & Michael Tsabar & Michael S. Cuoco & Liat Amir-Zilberstein & Heidie F. Cabanos & Jan-Christian Hütter & Bomiao Hu & Pratiksha I. Thakore & Marcin Tabaka & Charles P. Fulco & William Colgan, 2021. "Cycling cancer persister cells arise from lineages with distinct programs," Nature, Nature, vol. 596(7873), pages 576-582, August.
    4. Jaekyoung Son & Costas A. Lyssiotis & Haoqiang Ying & Xiaoxu Wang & Sujun Hua & Matteo Ligorio & Rushika M. Perera & Cristina R. Ferrone & Edouard Mullarky & Ng Shyh-Chang & Ya’an Kang & Jason B. Flem, 2013. "Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway," Nature, Nature, vol. 496(7443), pages 101-105, April.
    5. Jeffrey W. Tyner & Cristina E. Tognon & Daniel Bottomly & Beth Wilmot & Stephen E. Kurtz & Samantha L. Savage & Nicola Long & Anna Reister Schultz & Elie Traer & Melissa Abel & Anupriya Agarwal & Auro, 2018. "Functional genomic landscape of acute myeloid leukaemia," Nature, Nature, vol. 562(7728), pages 526-531, October.
    6. Won Dong Lee & Dzmitry Mukha & Elina Aizenshtein & Tomer Shlomi, 2019. "Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    5. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    10. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Justin N. Vaughn & Sandra E. Branham & Brian Abernathy & Amanda M. Hulse-Kemp & Adam R. Rivers & Amnon Levi & William P. Wechter, 2022. "Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Eliza S. Nieweglowska & Axel F. Brilot & Melissa Méndez-Moran & Claire Kokontis & Minkyung Baek & Junrui Li & Yifan Cheng & David Baker & Joseph Bondy-Denomy & David A. Agard, 2023. "The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Sash Lopaticki & Robyn McConville & Alan John & Niall Geoghegan & Shihab Deen Mohamed & Lisa Verzier & Ryan W. J. Steel & Cindy Evelyn & Matthew T. O’Neill & Niccolay Madiedo Soler & Nichollas E. Scot, 2022. "Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    15. Radoslaw Pluta & Eric Aragón & Nicholas A. Prescott & Lidia Ruiz & Rebeca A. Mees & Blazej Baginski & Julia R. Flood & Pau Martin-Malpartida & Joan Massagué & Yael David & Maria J. Macias, 2022. "Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Xinheng He & Lifen Zhao & Yinping Tian & Rui Li & Qinyu Chu & Zhiyong Gu & Mingyue Zheng & Yusong Wang & Shaoning Li & Hualiang Jiang & Yi Jiang & Liuqing Wen & Dingyan Wang & Xi Cheng, 2024. "Highly accurate carbohydrate-binding site prediction with DeepGlycanSite," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    18. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Mindaugas Margelevičius, 2024. "GTalign: spatial index-driven protein structure alignment, superposition, and search," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    20. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30223-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.