Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

CBL mutation in childhood therapy-related leukemia

Leukemia volume 25, pages 1356–1358 (2011)Cite this article

Subjects

Therapy-related leukemia and myelodysplastic syndrome (t-Leuk/MDS) are mainly caused by topoisomerase II inhibitors that cause acute myeloid leukemia (AML) with an 11q23 translocation or by alkylating agents that induce MDS/AML with an AML1 mutation and monosomy 7.1, 2 Two types of t-Leuk/MDS can be distinguished, one of which has a long latency (⩾5–7 years) and is seen following alkylating agents, frequently with an preleukemic phase.1 The other has a short latency period (1–3 years), no preleukemic phase, and is strongly associated with the administration of topoisomerase II inhibitors and chromosomal abnormalities involving 11q23 translocation/MLL rearrangement (MLL-R).2 Repair of etoposide (VP-16)-stabilized DNA topoisomerase II covalent complexes may initiate MLL-R observed in patients.3

In this regard, recent reports of somatic mutations of the CBL proto-oncogene in myeloid neoplasms are intriguing, because these CBL mutations were shown to result in aberrant tyrosine kinase signaling, which would lead also to activation of RAS signaling pathways. We and others reported that CBL mutations occurred in a variety of myeloid neoplasms, including de novo AML,4 MDS4 and myeloproliferative neoplasm,4, 5 especially in chronic myelomonocytic leukemia5 and juvenile myelomonocytic leukemia.6 The importance of CBL mutations concerning about leukemogenesis is substantially increased. This prompted us to search for possible CBL mutations in pediatric t-Leuk/MDS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Tucker MA, Meadows AT, Boice Jr JD, Stovall M, Oberlin O, Stone BJ et al. Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst 1987; 78: 459–464.

    Article  CAS  PubMed  Google Scholar 

  2. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC et al. Acute myeloid leukemias in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 1991; 325: 1682–1687.

    Article  CAS  PubMed  Google Scholar 

  3. Nakada S, Katsuki Y, Imoto I, Yokoyama T, Nagasawa M, Inazawa J et al. Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations. J Clin Invest 2006; 116: 80–89.

    Article  CAS  PubMed  Google Scholar 

  4. Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009; 113: 6182–6192.

    Article  CAS  Google Scholar 

  5. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009; 460: 904–908.

    Article  CAS  Google Scholar 

  6. Shiba N, Kato M, Park MJ, Sanada M, Ito E, Fukushima K et al. CBL mutations in juvenile myelomonocytic leukemia and pediatric myelodysplastic syndrome. Leukemia 2010; 24: 1090–1092.

    Article  CAS  PubMed  Google Scholar 

  7. Sugita K, Furukawa T, Tsuchida M, Okawa Y, Nakazawa S, Akatsuka J et al. High frequency of etoposide (VP-16)-related secondary leukemia in children with non-Hodgkin's lymphoma. Am J Pediatr Hematol Oncol 1993; 15: 99–104.

    Article  CAS  PubMed  Google Scholar 

  8. Fu JF, Hsu JJ, Tang TC, Shih LY . Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia. Genes Chromosomes Cancer 2003; 37: 214–219.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Mrs Chisato Murata and Miss Sayaka Takeuchi, for their excellent technical assistance. This work was supported by a grant for Cancer Research, a grant for Research on Children and Families, and Research on intractable diseases, Health and Labor Sciences Research Grants from the Ministry of Health, Labor, and Welfare of Japan, a Grant-in-Aid for Scientific Research (B, C) and Exploratory Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by a Research grant for Gunma Prefectural Hospitals.

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan

    N Shiba, M-j Park, M Sotomatsu & Y Hayashi

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

    N Shiba, T Kanazawa & H Arakawa

  3. Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan

    T Taki

  4. Department of Developmental Biology, Post Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    M Nagasawa

  5. Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    J Takita

  6. Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo, Japan,

    H Ohnishi

Authors
  1. N Shiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Taki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M-j Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Nagasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Kanazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Takita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Sotomatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Hayashi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiba, N., Taki, T., Park, Mj. et al. CBL mutation in childhood therapy-related leukemia. Leukemia 25, 1356–1358 (2011). https://doi.org/10.1038/leu.2011.75

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.75

This article is cited by

Search

Advanced search

Quick links