IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58662-0.html
   My bibliography  Save this article

Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes

Author

Listed:
  • Juan Jose Rodriguez-Sevilla

    (The University of MD Anderson Cancer Center)

  • Irene Ganan-Gomez

    (The University of MD Anderson Cancer Center)

  • Bijender Kumar

    (The University of Texas MD Anderson Cancer Center)

  • Natthakan Thongon

    (The University of MD Anderson Cancer Center)

  • Feiyang Ma

    (Northwestern University)

  • Kelly S. Chien

    (The University of MD Anderson Cancer Center)

  • Yi J. Kim

    (The University of MD Anderson Cancer Center)

  • Hui Yang

    (The University of MD Anderson Cancer Center)

  • Sanam Loghavi

    (The University of Texas MD Anderson Cancer Center)

  • Roselyn Tan

    (Moores Cancer Center)

  • Vera Adema

    (The University of MD Anderson Cancer Center)

  • Zongrui Li

    (The University of MD Anderson Cancer Center)

  • Tomoyuki Tanaka

    (The University of MD Anderson Cancer Center)

  • Hidetaka Uryu

    (The University of MD Anderson Cancer Center)

  • Rashmi Kanagal-Shamanna

    (The University of Texas MD Anderson Cancer Center)

  • Gheath Al-Atrash

    (The University of Texas MD Anderson Cancer Center)

  • Rafael Bejar

    (Moores Cancer Center)

  • Pinaki Prosad Banerjee

    (The University of Texas MD Anderson Cancer Center)

  • Sophia Lynn Cha

    (The University of Texas MD Anderson Cancer Center)

  • Guillermo Montalban-Bravo

    (The University of MD Anderson Cancer Center)

  • Max Dougherty

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Maria Claudina Fernandez Laurita

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Noelle Wheeler

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Baosen Jia

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Eirini P. Papapetrou

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Franco Izzo

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Daniela E. Dueñas

    (The University of Texas MD Anderson Cancer Center)

  • Salome McAllen

    (The University of Texas MD Anderson Cancer Center)

  • Yiqian Gu

    (University of California Los Angeles)

  • Gabriele Todisco

    (Humanitas University
    IRCCS Humanitas Research Hospital)

  • Francesca Ficara

    (IRCCS Humanitas Research Hospital
    National Research Council)

  • Matteo Giovanni Porta

    (Humanitas University
    IRCCS Humanitas Research Hospital)

  • Abhinav Jain

    (The University of MD Anderson Cancer Center)

  • Koichi Takahashi

    (The University of MD Anderson Cancer Center
    The University of MD Anderson Cancer Center)

  • Karen Clise-Dwyer

    (The University of Texas MD Anderson Cancer Center)

  • Stephanie Halene

    (Yale University School of Medicine)

  • Maria Teresa Sabrina Bertilaccio

    (The University of MD Anderson Cancer Center)

  • Guillermo Garcia-Manero

    (The University of MD Anderson Cancer Center)

  • May Daher

    (The University of Texas MD Anderson Cancer Center)

  • Simona Colla

    (The University of MD Anderson Cancer Center)

Abstract

Dissecting the preneoplastic disease states’ biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.

Suggested Citation

  • Juan Jose Rodriguez-Sevilla & Irene Ganan-Gomez & Bijender Kumar & Natthakan Thongon & Feiyang Ma & Kelly S. Chien & Yi J. Kim & Hui Yang & Sanam Loghavi & Roselyn Tan & Vera Adema & Zongrui Li & Tomo, 2025. "Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58662-0
    DOI: 10.1038/s41467-025-58662-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58662-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58662-0?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. Kiyomi Morita & Feng Wang & Katharina Jahn & Tianyuan Hu & Tomoyuki Tanaka & Yuya Sasaki & Jack Kuipers & Sanam Loghavi & Sa A. Wang & Yuanqing Yan & Ken Furudate & Jairo Matthews & Latasha Little & C, 2020. "Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Maxime Boy & Valeria Bisio & Lin-Pierre Zhao & Fabien Guidez & Bérénice Schell & Emilie Lereclus & Guylaine Henry & Juliette Villemonteix & Fernando Rodrigues-Lima & Katia Gagne & Christelle Retiere &, 2023. "Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Joseph A. Fraietta & Christopher L. Nobles & Morgan A. Sammons & Stefan Lundh & Shannon A. Carty & Tyler J. Reich & Alexandria P. Cogdill & Jennifer J. D. Morrissette & Jamie E. DeNizio & Shantan Redd, 2018. "Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells," Nature, Nature, vol. 558(7709), pages 307-312, June.
    5. Juan Jose Rodriguez-Sevilla & Irene Ganan-Gomez & Feiyang Ma & Kelly Chien & Monica Rey & Sanam Loghavi & Guillermo Montalban-Bravo & Vera Adema & Bethany Wildeman & Rashmi Kanagal-Shamanna & Alexandr, 2024. "Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes," Nature Communications, Nature, vol. 15(1), pages 1-5, December.
    6. Vrutant V. Shah & Aundrietta D. Duncan & Shiming Jiang & Sabrina A. Stratton & Kendra L. Allton & Clinton Yam & Abhinav Jain & Patrick M. Krause & Yue Lu & Shirong Cai & Yizheng Tu & Xinhui Zhou & Xia, 2021. "Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Yuanbin Song & Anthony Rongvaux & Ashley Taylor & Tingting Jiang & Toma Tebaldi & Kunthavai Balasubramanian & Arun Bagale & Yunus Kasim Terzi & Rana Gbyli & Xiaman Wang & Xiaoying Fu & Yimeng Gao & Ju, 2019. "A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    8. Shaima’a Hamarsheh & Olaf Groß & Tilman Brummer & Robert Zeiser, 2020. "Immune modulatory effects of oncogenic KRAS in cancer," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    9. Guillermo Serrano & Nerea Berastegui & Aintzane Díaz-Mazkiaran & Paula García-Olloqui & Carmen Rodriguez-Res & Sofia Huerga-Dominguez & Marina Ainciburu & Amaia Vilas-Zornoza & Patxi San Martin-Uriz &, 2024. "Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Róisín M. Loftus & Nadine Assmann & Nidhi Kedia-Mehta & Katie L. O’Brien & Arianne Garcia & Conor Gillespie & Jens L. Hukelmann & Peter J. Oefner & Angus I. Lamond & Clair M. Gardiner & Katja Dettmer , 2018. "Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    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. Peter Truong & Sylvie Shen & Swapna Joshi & Md Imtiazul Islam & Ling Zhong & Mark J. Raftery & Ali Afrasiabi & Hamid Alinejad-Rokny & Mary Nguyen & Xiaoheng Zou & Golam Sarower Bhuyan & Chowdhury H. S, 2024. "TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Juan Jose Rodriguez-Sevilla & Vera Adema & Kelly S. Chien & Sanam Loghavi & Feiyang Ma & Hui Yang & Guillermo Montalban-Bravo & Xuelin Huang & Xavier Calvo & Joby Joseph & Kristy Bodden & Guillermo Ga, 2024. "The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Hikaru Hayashi & Sayaka Seki & Takeshi Tomita & Masayoshi Kato & Norihiro Ashihara & Tokuhiro Chano & Hideki Sanjo & Miwa Kawade & Chenhui Yan & Hiroki Sakai & Hidenori Tomida & Miyuki Tanaka & Mai Iw, 2025. "Synthetic short mRNA prevents metastasis via innate-adaptive immunity," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    4. Xiangwei Li & Thomas Delerue & Ben Schöttker & Bernd Holleczek & Eva Grill & Annette Peters & Melanie Waldenberger & Barbara Thorand & Hermann Brenner, 2022. "Derivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Andreas Herchenröther & Stefanie Gossen & Tobias Friedrich & Alexander Reim & Nadine Daus & Felix Diegmüller & Jörg Leers & Hakimeh Moghaddas Sani & Sarah Gerstner & Leah Schwarz & Inga Stellmacher & , 2023. "The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Hao A. Duong & Kenkichi Baba & Jason P. DeBruyne & Alec J. Davidson & Christopher Ehlen & Michael Powell & Gianluca Tosini, 2024. "Environmental circadian disruption re-writes liver circadian proteomes," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    8. Li Guo & Cheng Hu & Yang Liu & Xiaoyu Chen & Deli Song & Runling Shen & Zhanzhen Liu & Xudong Jia & Qinfen Zhang & Yuanzhu Gao & Zhezhi Deng & Tao Zuo & Jun Hu & Wenbo Zhu & Jing Cai & Guangmei Yan & , 2023. "Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Cecilia Pessoa Rodrigues & Aindrila Chatterjee & Meike Wiese & Thomas Stehle & Witold Szymanski & Maria Shvedunova & Asifa Akhtar, 2021. "Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    10. Tianshi Feng & Xuemei Zhao & Ping Gu & Wah Yang & Cunchuan Wang & Qingyu Guo & Qiaoyun Long & Qing Liu & Ying Cheng & Jin Li & Cynthia Kwan Yui Cheung & Donghai Wu & Xinyu Kong & Yong Xu & Dewei Ye & , 2022. "Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Elisa Bellucci & Andrea Benazzo & Chunming Xu & Elena Bitocchi & Monica Rodriguez & Saleh Alseekh & Valerio Di Vittori & Tania Gioia & Kerstin Neumann & Gaia Cortinovis & Giulia Frascarelli & Ester Mu, 2023. "Selection and adaptive introgression guided the complex evolutionary history of the European common bean," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Jiayin Peng & Lili Han & Biao Liu & Jiawen Song & Yuang Wang & Kunpeng Wang & Qian Guo & XinYan Liu & Yu Li & Jujin Zhang & Wenqing Wu & Sheng Li & Xin Fu & Cheng-le Zhuang & Weikang Zhang & Shengbao , 2023. "Gli1 marks a sentinel muscle stem cell population for muscle regeneration," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Lisa Willemsen & Jiyeun Lee & Pramod Shinde & Ferran Soldevila & Minori Aoki & Shelby Orfield & Mari Kojima & Ricardo Silva Antunes & Alessandro Sette & Bjoern Peters, 2025. "Th1 polarization in Bordetella pertussis vaccine responses is maintained through a positive feedback loop," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    14. Brent S. Perlman & Noah Burget & Yeqiao Zhou & Gregory W. Schwartz & Jelena Petrovic & Zora Modrusan & Robert B. Faryabi, 2024. "Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    15. Elisa Setten & Alessandra Castagna & Josué Manik Nava-Sedeño & Jonathan Weber & Roberta Carriero & Andreas Reppas & Valery Volk & Jessica Schmitz & Wilfried Gwinner & Haralampos Hatzikirou & Friedrich, 2022. "Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    16. Andrea Zanetti & Gwendal Dujardin & Lucas Fares-Taie & Jeanne Amiel & Jérôme E. Roger & Isabelle Audo & Matthieu P. Robert & Pierre David & Vincent Jung & Nicolas Goudin & Ida Chiara Guerrera & Stépha, 2024. "GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    17. Dafne Ibarra-Morales & Michael Rauer & Piergiuseppe Quarato & Leily Rabbani & Fides Zenk & Mariana Schulte-Sasse & Francesco Cardamone & Alejandro Gomez-Auli & Germano Cecere & Nicola Iovino, 2021. "Histone variant H2A.Z regulates zygotic genome activation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    18. Xueguang Zhang & Gelin Huang & Ting Jiang & Lanlan Meng & Tongtong Li & Guohui Zhang & Nan Wu & Xinyi Chen & Bingwang Zhao & Nana Li & Sixian Wu & Junceng Guo & Rui Zheng & Zhiliang Ji & Zhigang Xu & , 2024. "CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    19. Ryuki Shimada & Yuzuru Kato & Naoki Takeda & Sayoko Fujimura & Kei-ichiro Yasunaga & Shingo Usuki & Hitoshi Niwa & Kimi Araki & Kei-ichiro Ishiguro, 2023. "STRA8–RB interaction is required for timely entry of meiosis in mouse female germ cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Xiang He & Daiqin Xiong & Lei Zhao & Jialong Fu & Lingfei Luo, 2024. "Meningeal lymphatic supporting cells govern the formation and maintenance of zebrafish mural lymphatic endothelial cells," Nature Communications, Nature, vol. 15(1), pages 1-15, 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:16:y:2025:i:1:d:10.1038_s41467-025-58662-0. 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.