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ACUTE MYELOID LEUKEMIA

KRAS G12 mutations as adverse prognostic factors in KMT2A-rearranged acute myeloid leukemia

Leukemia (2024)Cite this article

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Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease characterized by uncontrolled proliferation of hematopoietic precursor cells [1]. KMT2A (MLL) rearrangements are among the most frequent chromosomal abnormalities in AML [2]. The proportion of KMT2A rearrangements is higher in infants/children with AML [3]. KMT2A-rearranged (KMT2A-r) AML is also heterogeneous, with >60 different fusion partner genes identified [4]. The prognosis of patients with KMT2A-r AML varies based on the KMT2A fusion pattern [5]. Therefore, some fusion patterns are currently used for risk stratification of AML treatment [6]. In KMT2A-r AML, RAS pathway genes are frequently mutated [7, 8]. Our recent study identified mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene as adverse prognostic factors in KMT2A-r AML [9]. However, the effect of the location of KRAS mutations on prognosis remains unclear because of the small sample size.

In this study, targeted sequencing was performed in samples from patients enrolled in the Japan Children’s Cancer Group (JCCG) AML-99/AML-05/AML-12 studies, which was analyzed using the data in the TARGET-AML cohort [3]. Then, we examined the prognostic significance of KRAS mutations based on their location in patients with KMT2A-r AML (n = 225) and non-KMT2A-r AML (n = 882). For further information on patients and study protocol, DNA sequencing and mutation calling, and statistical analysis, please refer to Supplemental Methods. This study was conducted following the principles defined in the Declaration of Helsinki and approved by the ethics committees of all participating institutions, the Kyoto University Medical Ethics Committee, and the JCCG Research Review Committee (approval numbers: G0361 and 106). All patients, or their parents or guardians, provided written informed consent.

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Fig. 1: KRAS G12 mutations as prognostic factors in KMT2A-r AML.

Data availability

The datasets used in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank Dr. Hiroo Ueno (Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan) for supporting sequencing analysis. This work was supported by a Grant-in-Aid from the Agency for Medical Research and Development (Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT), Project for Cancer Research and Therapeutic Evolution (P-CREATE), and Practical Research for Innovative Cancer Control) and JSPS KAKENHI (JP19K16832, JP22K08475, and JP23K07264). Supercomputing resources were provided by the Human Genome Center, Institute of Medical Science, University of Tokyo. We thank all participating doctors and patients who were involved in the JCCG AML-99/AML-05/AML-12 studies.

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Author notes

  1. These authors contributed equally: Shinju Iyoda, Kenichi Yoshida, Kota Shoji.

Authors and Affiliations

  1. Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shinju Iyoda, Kota Shoji, Nana Ito, Miu Tanaka, Momoko Nishikori, Souichi Adachi & Hidemasa Matsuo

  2. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenichi Yoshida, Yasuhito Nannya & Seishi Ogawa

  3. Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan

    Kenichi Yoshida

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

    Yasuhito Nannya

  5. Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan

    Genki Yamato

  6. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Shinichi Tsujimoto & Norio Shiba

  7. Institute of Physiology and Medicine, Jobu University, Takasaki, Japan

    Yasuhide Hayashi

  8. Laboratory of Molecular Analysis, Nippon Medical School, Tokyo, Japan

    Yusuke Shiozawa

  9. Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan

    Yuichi Shiraishi, Kenichi Chiba & Ai Okada

  10. Department of Integrated Analytics, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan

    Hiroko Tanaka & Satoru Miyano

  11. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yuhki Koga

  12. Division of Hematology/Oncology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Hiroaki Goto

  13. Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Hiroshi Moritake

  14. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Kiminori Terui & Etsuro Ito

  15. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    Nobutaka Kiyokawa

  16. Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Daisuke Tomizawa

  17. Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan

    Takashi Taga

  18. Department of Pediatrics, Higashiosaka Aramoto Heiwa Clinic, Higashiosaka, Japan

    Akio Tawa

  19. Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junko Takita

  20. Shiga General Hospital, Moriyama, Japan

    Souichi Adachi

  21. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Hidemasa Matsuo

Authors
  1. Shinju Iyoda
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  2. Kenichi Yoshida
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Contributions

SI, KY, KS, and H Matsuo analyzed the clinical and sequencing data; NI and MT helped with the analysis; YN, GY, ST, NS, and YH performed sequencing; Y Shiozawa, Y Shiraishi, KC, AO, HT, and SM developed sequence data processing pipelines; YK, HG, H Moritake, KT, EI, NK, DT, TT, AT, JT, and SA collected clinical samples; KY, MN, SA, SO, and H Matsuo supervised the project. SI, KY, KS, and H Matsuo wrote the manuscript.

Corresponding author

Correspondence to Hidemasa Matsuo.

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Competing interests

SO: Leadership position/advisory role for Eisai, Chordia Therapeutics. Stockholder in: Asahi Genomics. Grant/Research funding from Chordia Therapeutics, Otsuka Pharmaceutical, Eisai. The remaining authors declare no competing financial interests.

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Iyoda, S., Yoshida, K., Shoji, K. et al. KRAS G12 mutations as adverse prognostic factors in KMT2A-rearranged acute myeloid leukemia. Leukemia (2024). https://doi.org/10.1038/s41375-024-02244-4

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