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Nature 460, 904-908 (13 August 2009) | doi:10.1038/nature08240; Received 9 October 2008; Accepted 30 June 2009; Published online 20 July 2009

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Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms

Masashi Sanada1,5,19, Takahiro Suzuki7,19, Lee-Yung Shih8,19, Makoto Otsu9, Motohiro Kato1,2, Satoshi Yamazaki6, Azusa Tamura1, Hiroaki Honda11, Mamiko Sakata-Yanagimoto12, Keiki Kumano3, Hideaki Oda13, Tetsuya Yamagata14, Junko Takita1,2,3, Noriko Gotoh10, Kumi Nakazaki1,4, Norihiko Kawamata15, Masafumi Onodera16, Masaharu Nobuyoshi7, Yasuhide Hayashi17, Hiroshi Harada18, Mineo Kurokawa3,4, Shigeru Chiba12, Hiraku Mori18, Keiya Ozawa7, Mitsuhiro Omine18, Hisamaru Hirai3,4, Hiromitsu Nakauchi6,9, H. Phillip Koeffler15 & Seishi Ogawa1,5

  1. Cancer Genomics Project,
  2. Department of Pediatrics,
  3. Cell Therapy and Transplantation Medicine, and,
  4. Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
  5. Core Research for Evolutional Science and Technology,
  6. Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
  7. Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan
  8. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Road, Taipei 105, Taiwan
  9. Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine,
  10. Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
  11. Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
  12. Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tukuba-shi, Ibaraki, 305-8571, Japan
  13. Department of Pathology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
  14. Department of Hematology, Dokkyo University School of Medicine, 800 Kitabayashi, Mibu, Tochigi 321-0293, Japan
  15. Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
  16. Department of Genetics, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
  17. Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa-shi, Gunma 377-8577, Japan
  18. Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan
  19. These authors contributed equally to this work.

Correspondence to: Lee-Yung Shih8,19Seishi Ogawa1,5 Correspondence and requests for materials should be addressed to S.O. (Email: sogawa-tky@umin.ac.jp) or L.-Y.S. (Email: sly7012@adm.cgmh.org.tw).

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Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes1, but also with gain-of-function mutations of proto-oncogenes2. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases3, 4, 5, 6. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl-/- haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl+/+ HSPCs, and transduction of C-CBL mutants into c-Cbl-/- HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl+/+ background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.

  1. Cancer Genomics Project,
  2. Department of Pediatrics,
  3. Cell Therapy and Transplantation Medicine, and,
  4. Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
  5. Core Research for Evolutional Science and Technology,
  6. Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
  7. Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan
  8. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Road, Taipei 105, Taiwan
  9. Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine,
  10. Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
  11. Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
  12. Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tukuba-shi, Ibaraki, 305-8571, Japan
  13. Department of Pathology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
  14. Department of Hematology, Dokkyo University School of Medicine, 800 Kitabayashi, Mibu, Tochigi 321-0293, Japan
  15. Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
  16. Department of Genetics, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
  17. Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa-shi, Gunma 377-8577, Japan
  18. Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan
  19. These authors contributed equally to this work.

Correspondence to: Lee-Yung Shih8,19Seishi Ogawa1,5 Correspondence and requests for materials should be addressed to S.O. (Email: sogawa-tky@umin.ac.jp) or L.-Y.S. (Email: sly7012@adm.cgmh.org.tw).