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NUP98 rearrangements in adult AML patients: evaluation of clinical implications and identification of novel fusion partners

Leukemia (2026)Cite this article

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Abstract

NUP98 rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with NUP98 rearrangements among 1569 AML cases, representing the majority of 44 NUP98-rearranged cases detected across 4753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with NUP98::NSD1 and NUP98::HOXA9 being the most frequent. Notably, two novel fusions—NUP98::MEOX2 and NUP98::HOXA6—were identified. Co-mutations were relatively infrequent; FLT3-ITD and WT1 mutations were the most common, while NPM1 mutations were exclusive. FLT3-ITD was significantly enriched in NUP98::NSD1 cases, whereas TET2 mutations were more frequent in NUP98::HOXA9 cases. Clonal hierarchy analysis suggested that NUP98 rearrangements occur early in leukemogenesis. NUP98-rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, NUP98::NSD1 was associated with a poor induction response, whereas NUP98::HOXA9 and NUP98 fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of NUP98-rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.

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Fig. 1: Molecular characteristics of AML with novel NUP98 rearrangements identified in this study.
Fig. 2: Genetic characteristics of adult AML patients with and without NUP98 rearrangements.
Fig. 3: Response rate and survival of adult AML patients with and without NUP98 rearrangements.
Fig. 4: Impact of co-mutations on survival in adult patients with NUP98-rearranged AML.
Fig. 5: Impact of NUP98 rearrangements and ELN 2022 risk classification on survival.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

The authors acknowledge the patients who participated in this study and their families. The authors thank the clinical research staff and caregivers at all participating sites. In preparing this work, ChatGPT was used to proofread the manuscript.

Funding

This work was supported in part by grants from the Japan Agency for Medical Research and Development (JP19cm0106235h0002, JP22bm0804004h0006 (K.C. and Y.Y.), JP15cm0106056h0005, JP19cm0106501h0004, JP16ck0106073h0003, JP19ck0106250h0003 (S.O.), JP19ck0106353h0003 (Y.Nannya.)), Core Research for Evolutional Science and Technology (JP19gm1110011) (S.O.), and JSPS KAKENHI (JP21K08414 (K.C.), JP25H01055 (M.S.-Y)), a grant from the Kobayashi Foundation for Cancer Research (K.C.), and a grant from the International Joint Usage/Research Center, IMSUT (24-2103 (K.C. and Y.Nannya).

Author information

Author notes

  1. These authors contributed equally: Kazuhisa Chonabayashi, Makoto Iwasaki.

Authors and Affiliations

  1. Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kazuhisa Chonabayashi, Makoto Iwasaki, Junya Kanda, Takahito Kawata, Maki Sakurada & Akifumi Takaori-Kondo

  2. Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    Kazuhisa Chonabayashi & Yoshinori Yoshida

  3. Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hiroyuki Takamori & Yasuhito Nannya

  4. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan

    Akinori Yoda, Seishi Ogawa & Yasuhito Nannya

  5. Department of Hematology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan

    Takahito Kawata & Mitsumasa Watanabe

  6. Department of Clinical Laboratory, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan

    Shumpei Mizuta

  7. Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan

    Tadakazu Kondo & Nobuhiro Hiramoto

  8. Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan

    Yasunori Ueda

  9. Department of Hematology, Tokyo Medical University, Tokyo, Japan

    Akihiko Gotoh

  10. Department of Hematology, Gifu Municipal Hospital, Gifu, Japan

    Senji Kasahara

  11. Laboratory of Pharmaceutical Health Care and Promotion, Gifu Pharmaceutical University, Gifu, Japan

    Senji Kasahara

  12. Japan Adult Leukemia Study Group (JALSG), Osaka, Japan

    Yuichi Ishikawa & Hitoshi Kiyoi

  13. Department of Hematology, Japanese Red Cross Osaka Hospital, Osaka, Japan

    Kazunori Imada

  14. Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan

    Kinuko Mitani

  15. Department of Hematology, Medical Research Institute Kitano Hospital, Osaka, Japan

    Toshiyuki Kitano

  16. Department of Hematology, Shinko Hospital, Hyogo, Japan

    Nobuyoshi Arima

  17. The Center for Hematological Diseases, Takeda General Hospital, Kyoto, Japan

    Yukiharu Nakabo

  18. Department of Hematology, Chugoku Central Hospital, Hiroshima, Japan

    Nobuo Sezaki

  19. Department of Hematology and Infectious Disease, Gifu University Hospital, Gifu, Japan

    Nobuhiro Kanemura

  20. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  21. Department of Hematology, NTT Medical Center, Tokyo, Tokyo, Japan

    Motoshi Ichikawa

  22. Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

    Yasushi Miyazaki

  23. Department of Hematology, Osaka International Cancer Institute, Osaka, Japan

    Shigeo Fuji

  24. Department of Hematology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan

    Mamiko Sakata-Yanagimoto

  25. Department of Hematology, University of Tsukuba Hospital, Division of Advanced Hemato-Oncology, Tsukuba, Japan

    Mamiko Sakata-Yanagimoto

  26. Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan

    Mamiko Sakata-Yanagimoto

Authors
  1. Kazuhisa Chonabayashi
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  2. Makoto Iwasaki
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Contributions

KC, M.Iwasaki, JK, and Y.Nannya conceived and designed the study and wrote the manuscript. KC, M.Iwasaki, and Y.Nannya collected and curated the data. SO and Y.Nannya performed targeted-capture sequencing. HT, AY, SO, and Y.Nannya analyzed and interpreted the sequencing data. KC performed most of the experiments. T.Kawata, SM, and YY performed some experiments. MS, T.Kondo, TH, YU, AG, MW, SK, Y.I., HK, KI, KM, T.Kitano, YT, Y.Nakabou, NS, NK, TF, M.Ichikawa, YM, SF, MS-Y, and AT-K collected patient samples and data. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Yasuhito Nannya.

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Chonabayashi, K., Iwasaki, M., Kanda, J. et al. NUP98 rearrangements in adult AML patients: evaluation of clinical implications and identification of novel fusion partners. Leukemia (2026). https://doi.org/10.1038/s41375-025-02848-4

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