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Chronic myleproliferative neoplasms

A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease

Leukemia volume 29, pages 2355–2365 (2015)Cite this article

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Abstract

Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14–15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs.

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Acknowledgements

We thank Profs Zhu Chen for carefully revising the paper and guiding the work and Qiang Li critical reading of the manuscript, all members of the Laboratory of Development and Disease (LDD) for their technical assistance and helpful discussions, and for Drs Anskar Leung and Bai-Liang He for sharing the flt3 morpholino. This work was supported in part by Chinese National Key Basic Research Project (2013CB966800, 2011CB964803), Special Grant of Ministry of Health (201202003), Mega-projects of Science Research for the 12th Five-Year Plan (2013ZX09303302) and the National Natural Science Foundation of China (81123005).

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  1. X Peng, M Dong and L Ma: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China

    X Peng, L Ma, J Mao, Y Chen, X Liu, T Du, Y Jin, Q Huang, K Li, T Liu, X Xi & S Chen

  2. Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China

    M Dong, X-E Jia, C Jin, L Gao, K Ma, L Wang, T Liu, M Deng & Y Zhou

  3. Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China

    L Ma

  4. Stem Cell Program at Boston Children’s Hospital, Hematology/Oncology Program at Children's Hospital and Dana Faber Cancer Institute, Harvard Medical School, Boston, MA, USA

    L I Zon & Y Zhou

  5. Howard Hughes Medical Institute, Boston, MA, USA

    L I Zon

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Correspondence to M Deng, Y Zhou, Y Zhou or S Chen.

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Peng, X., Dong, M., Ma, L. et al. A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease. Leukemia 29, 2355–2365 (2015). https://doi.org/10.1038/leu.2015.154

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