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Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study

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Abstract

We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.

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Funding

This study financially was supported by Grants-in-Aid from the Scientific Research Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17K09921), and from the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (17ck0106251).

Author information

Author notes

  1. Naomi Kawashima, Akimi Akashi, Yasunobu Nagata, Rika Kihara, and Yuichi Ishikawa contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, 466-8550, Japan

    Naomi Kawashima, Akimi Akashi, Rika Kihara, Yuichi Ishikawa & Hitoshi Kiyoi

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

    Yasunobu Nagata & Seishi Ogawa

  3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Yasunobu Nagata

  4. Department of Hematology, International Medical Center, Saitama Medical University, Hidaka, Japan

    Norio Asou

  5. Kanazawa University, Kanazawa, Japan

    Shigeki Ohtake

  6. Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan

    Shuichi Miyawaki

  7. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Toru Sakura

  8. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  9. Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

    Noriko Usui

  10. Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan

    Heiwa Kanamori

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

    Yoshikazu Ito

  12. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Kiyotoshi Imai

  13. Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Youko Suehiro

  14. Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan

    Kunio Kitamura

  15. Department of Hematology, Chiba University Hospital, Chiba, Japan

    Emiko Sakaida

  16. Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Akihiro Takeshita

  17. Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan

    Hitoshi Suzushima

  18. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Tomoki Naoe

  19. Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, Osaka, Japan

    Itaru Matsumura

  20. Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Yasushi Miyazaki

Authors
  1. Naomi Kawashima
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  2. Akimi Akashi
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  3. Yasunobu Nagata
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  5. Yuichi Ishikawa
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  9. Toru Sakura
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  10. Yukiyasu Ozawa
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  11. Noriko Usui
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  12. Heiwa Kanamori
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  13. Yoshikazu Ito
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  14. Kiyotoshi Imai
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  18. Akihiro Takeshita
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  19. Hitoshi Suzushima
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  21. Itaru Matsumura
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  22. Yasushi Miyazaki
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  23. Seishi Ogawa
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  24. Hitoshi Kiyoi
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for the Japan Adult Leukemia Study Group (JALSG)

Corresponding author

Correspondence to Hitoshi Kiyoi.

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Conflict of interest

H. Kiyoi received research funding from Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Kyowa Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., FUJIFILM Corporation, Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc. and Celgene Corporation, consulting fees from Astellas Pharma Inc. and Daiichi Sankyo Co., Ltd., and honoraria from Bristol-Myers Squibb and Pfizer Japan Inc., N.A. received research funding from Chugai Pharmaceutical Co., Ltd. and Astellas Pharma Inc., S.M. received honoraria from Astellas Pharma Inc. and Otsuka Pharmaceutical Co., Ltd., N.U. received research funding from Nippon Shinyaku Pharmaceutical Co., Ltd., Novartis Pharma, Bristol-Myers Squibb, Celgene Corporation, Fujimoto Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc. and Sysmex Co., Ltd., consulting fees from Celgene Corporation, Fujimoto Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc. and Sysmex Co., Ltd., Astellas Pharma Inc., CIMIC Co., Ltd., Eli Lilly Japan, Huya Bioscience International, Janssen Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Nippon Boehiringer Ingleheim Co., Ltd., SymBio Pharmaceuticals Co., Ltd., Takeda Bio Development Center Ltd. and Zenyaku Kogyo Co., Ltd., and honoraria from Bristol-Myers Squibb, Celgene Co., Ltd., Pfizer Japan Inc., Sysmex Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co., Ltd. AT received research funding from Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Pfizer Japan Inc. and Takeda Pharmaceutical Co Ltd. T.N. received research funding from FUJIFILM Corporation, Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., Dainippon Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd. and Toyama Chemical Co., Ltd., patents and royalties from FUJIFILM Corporation, and honoraria from Nippon Boehringer Ingelheim Co., Ltd. and Otsuka Pharmaceutical Co., Ltd., and I.M. received honoraria from Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co., Ltd. The other authors have no relevant conflicts to disclose.

Ethical approval

This study was approved by the institutional review board of each participating institution. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Kawashima, N., Akashi, A., Nagata, Y. et al. Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. Ann Hematol 98, 83–91 (2019). https://doi.org/10.1007/s00277-018-3492-5

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