IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26420-7.html
   My bibliography  Save this article

Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Author

Listed:
  • Lianjun Zhang

    (City of Hope Medical Center)

  • Le Xuan Truong Nguyen

    (City of Hope Medical Center)

  • Ying-Chieh Chen

    (City of Hope Medical Center)

  • Dijiong Wu

    (First Affiliated Hospital of Zhejiang Chinese Medical University)

  • Guerry J. Cook

    (City of Hope Medical Center)

  • Dinh Hoa Hoang

    (City of Hope Medical Center)

  • Casey J. Brewer

    (City of Hope Medical Center)

  • Xin He

    (City of Hope Medical Center)

  • Haojie Dong

    (City of Hope Medical Center)

  • Shu Li

    (Zhejiang University School of Medicine)

  • Man Li

    (City of Hope Medical Center)

  • Dandan Zhao

    (City of Hope Medical Center)

  • Jing Qi

    (City of Hope Medical Center)

  • Wei-Kai Hua

    (City of Hope Medical Center)

  • Qi Cai

    (City of Hope Medical Center)

  • Emily Carnahan

    (City of Hope Medical Center)

  • Wei Chen

    (City of Hope Medical Center)

  • Xiwei Wu

    (City of Hope Medical Center)

  • Piotr Swiderski

    (City of Hope Medical Center)

  • Russell C. Rockne

    (City of Hope Medical Center)

  • Marcin Kortylewski

    (City of Hope Medical Center)

  • Ling Li

    (City of Hope Medical Center)

  • Bin Zhang

    (City of Hope Medical Center)

  • Guido Marcucci

    (City of Hope Medical Center)

  • Ya-Huei Kuo

    (City of Hope Medical Center)

Abstract

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.

Suggested Citation

  • Lianjun Zhang & Le Xuan Truong Nguyen & Ying-Chieh Chen & Dijiong Wu & Guerry J. Cook & Dinh Hoa Hoang & Casey J. Brewer & Xin He & Haojie Dong & Shu Li & Man Li & Dandan Zhao & Jing Qi & Wei-Kai Hua , 2021. "Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26420-7
    DOI: 10.1038/s41467-021-26420-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26420-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26420-7?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. Jing Zhang & Donghoon Lee & Vineet Dhiman & Peng Jiang & Jie Xu & Patrick McGillivray & Hongbo Yang & Jason Liu & William Meyerson & Declan Clarke & Mengting Gu & Shantao Li & Shaoke Lou & Jinrui Xu &, 2020. "An integrative ENCODE resource for cancer genomics," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Toru Wakioka & Atsuo Sasaki & Reiko Kato & Takanori Shouda & Akira Matsumoto & Kanta Miyoshi & Makoto Tsuneoka & Setsuro Komiya & Roland Baron & Akihiko Yoshimura, 2001. "Spred is a Sprouty-related suppressor of Ras signalling," Nature, Nature, vol. 412(6847), pages 647-651, August.
    3. Victor Ambros, 2004. "The functions of animal microRNAs," Nature, Nature, vol. 431(7006), pages 350-355, September.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Matteo Marchesini & Andrea Gherli & Elisa Simoncini & Lucas Moron Dalla Tor & Anna Montanaro & Natthakan Thongon & Federica Vento & Chiara Liverani & Elisa Cerretani & Anna D’Antuono & Luca Pagliaro &, 2024. "Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

    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. Michelle Dietzen & Haoran Zhai & Olivia Lucas & Oriol Pich & Christopher Barrington & Wei-Ting Lu & Sophia Ward & Yanping Guo & Robert E. Hynds & Simone Zaccaria & Charles Swanton & Nicholas McGranaha, 2024. "Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. José María Galván-Román & Ángel Lancho-Sánchez & Sergio Luquero-Bueno & Lorena Vega-Piris & Jose Curbelo & Marcos Manzaneque-Pradales & Manuel Gómez & Hortensia de la Fuente & Mara Ortega-Gómez & Javi, 2020. "Usefulness of circulating microRNAs miR-146a and miR-16-5p as prognostic biomarkers in community-acquired pneumonia," PLOS ONE, Public Library of Science, vol. 15(10), pages 1-13, October.
    3. Kshitij Srivastava & Anvesha Srivastava, 2012. "Comprehensive Review of Genetic Association Studies and Meta-Analyses on miRNA Polymorphisms and Cancer Risk," PLOS ONE, Public Library of Science, vol. 7(11), pages 1-1, November.
    4. Yanyan Wang & Yujie Zhang & Chi Pan & Feixia Ma & Suzhan Zhang, 2015. "Prediction of Poor Prognosis in Breast Cancer Patients Based on MicroRNA-21 Expression: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-13, February.
    5. Charlotte Glinge & Sebastian Clauss & Kim Boddum & Reza Jabbari & Javad Jabbari & Bjarke Risgaard & Philipp Tomsits & Bianca Hildebrand & Stefan Kääb & Reza Wakili & Thomas Jespersen & Jacob Tfelt-Han, 2017. "Stability of Circulating Blood-Based MicroRNAs – Pre-Analytic Methodological Considerations," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-16, February.
    6. Hossain Ahmed & Beyene Joseph, 2013. "Estimation of weighted log partial area under the ROC curve and its application to MicroRNA expression data," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 12(6), pages 743-755, December.
    7. Zhide Fang & Ruofei Du & Andrea Edwards & Erik K Flemington & Kun Zhang, 2013. "The Sequence Structures of Human MicroRNA Molecules and Their Implications," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-9, January.
    8. Hai Lian & Lei Wang & Jingmin Zhang, 2012. "Increased Risk of Breast Cancer Associated with CC Genotype of Has-miR-146a Rs2910164 Polymorphism in Europeans," PLOS ONE, Public Library of Science, vol. 7(2), pages 1-7, February.
    9. Le Thi Truc Linh, 2018. "The Microrna 29 family and its regulation," HO CHI MINH CITY OPEN UNIVERSITY JOURNAL OF SCIENCE - ENGINEERING AND TECHNOLOGY, HO CHI MINH CITY OPEN UNIVERSITY JOURNAL OF SCIENCE, HO CHI MINH CITY OPEN UNIVERSITY, vol. 8(1), pages 18-27.
    10. Seyedehsadaf Asfa & Halil Ibrahim Toy & Reza Arshinchi Bonab & George P. Chrousos & Athanasia Pavlopoulou & Styliani A. Geronikolou, 2023. "Soft Tissue Ewing Sarcoma Cell Drug Resistance Revisited: A Systems Biology Approach," IJERPH, MDPI, vol. 20(13), pages 1-17, July.
    11. Orso Maria Lucherini & Laura Obici & Manuela Ferracin & Valerio Fulci & Michael F McDermott & Giampaolo Merlini & Isabella Muscari & Flora Magnotti & Laura J Dickie & Mauro Galeazzi & Massimo Negrini , 2013. "First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)," PLOS ONE, Public Library of Science, vol. 8(9), pages 1-6, September.
    12. Wei Meng & Joseph P McElroy & Stefano Volinia & Jeff Palatini & Sarah Warner & Leona W Ayers & Kamalakannan Palanichamy & Arnab Chakravarti & Tim Lautenschlaeger, 2013. "Comparison of MicroRNA Deep Sequencing of Matched Formalin-Fixed Paraffin-Embedded and Fresh Frozen Cancer Tissues," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-9, May.
    13. Li Li & Yunjian Sheng & Lin Lv & Jian Gao, 2013. "The Association between Two MicroRNA Variants (miR-499, miR-149) and Gastrointestinal Cancer Risk: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.
    14. Blanca Elena Castro-Magdonel & Manuela Orjuela & Diana E Alvarez-Suarez & Javier Camacho & Lourdes Cabrera-Muñoz & Stanislaw Sadowinski-Pine & Aurora Medina-Sanson & Citlali Lara-Molina & Daphne Garcí, 2020. "Circulating miRNome detection analysis reveals 537 miRNAS in plasma, 625 in extracellular vesicles and a discriminant plasma signature of 19 miRNAs in children with retinoblastoma from which 14 are al," PLOS ONE, Public Library of Science, vol. 15(4), pages 1-19, April.
    15. Adam Emmer, 2019. "The careers behind and the impact of solo author articles in Nature and Science," Scientometrics, Springer;Akadémiai Kiadó, vol. 120(2), pages 825-840, August.
    16. Guang Shi & D. Thirumalai, 2023. "A maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Wei Li & Jing Wang & Qiu-Dan Chen & Xu Qian & Qi Li & Yu Yin & Zhu-Mei Shi & Lin Wang & Jie Lin & Ling-Zhi Liu & Bing-Hua Jiang, 2013. "Insulin Promotes Glucose Consumption via Regulation of miR-99a/mTOR/PKM2 Pathway," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-8, June.
    18. Junpeng Zhang & Taosheng Xu & Lin Liu & Wu Zhang & Chunwen Zhao & Sijing Li & Jiuyong Li & Nini Rao & Thuc Duy Le, 2020. "LMSM: A modular approach for identifying lncRNA related miRNA sponge modules in breast cancer," PLOS Computational Biology, Public Library of Science, vol. 16(4), pages 1-22, April.
    19. Hisakazu Iwama & Kiyohito Kato & Hitomi Imachi & Koji Murao & Tsutomu Masaki, 2018. "Human microRNAs preferentially target genes with intermediate levels of expression and its formation by mammalian evolution," PLOS ONE, Public Library of Science, vol. 13(5), pages 1-20, May.
    20. Jiali Xu & Zhiqiang Yin & Hong Shen & Wen Gao & Yingying Qian & Dong Pei & Lingxiang Liu & Yongqian Shu, 2013. "A Genetic Polymorphism in pre-miR-27a Confers Clinical Outcome of Non-Small Cell Lung Cancer in a Chinese Population," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-8, November.

    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:12:y:2021:i:1:d:10.1038_s41467-021-26420-7. 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.