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Molecular targets for therapy

Constitutively active ABL family kinases, TEL/ABL and TEL/ARG, harbor distinct leukemogenic activities in vivo

Leukemia volume 31, pages 2742–2751 (2017)Cite this article

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Abstract

ABL (ABL1) and ARG (ABL2) are highly homologous to each other in overall domain structure and amino-acid sequence, with the exception of their C termini. As with ABL, translocations that fuse ARG to ETV6/TEL have been identified in patients with leukemia. To assess the in vivo leukemogenic activity of constitutively active ABL and ARG, we generated a bone marrow (BM) transplantation model using the chimeric forms TEL/ABL and TEL/ARG, which have comparable kinase activities. TEL/ABL rapidly induced fatal myeloid leukemia in recipient mice, whereas recipients of TEL/ARG-transduced cells did not develop myeloid leukemia, instead, they succumbed to a long-latency infiltrative mastocytosis that could be adoptively transferred to secondary recipients. Swapping of the C termini of ABL and ARG altered disease latency and phenotypes. In a detailed in vitro study, TEL/ARG strongly promoted mast cell differentiation in response to stem cell factor or interleukin-3, whereas TEL/ABL preferentially induced myeloid differentiation of hematopoietic stem/progenitor cells. These results indicate that ABL and ARG kinase activate distinct differentiation pathways to induce specific diseases in vivo, that is, myeloid leukemia and mastocytosis, respectively. Further elucidation of the differences in their properties should provide important insight into the pathogenic mechanisms of oncogenes of the ABL kinase family.

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Acknowledgements

We are grateful to Dr Eiichi Morii at Osaka University, Dr Tatsuki R Kataoka at Kyoto University and Dr Yukihiko Kitamura at Shionogi & Co., Ltd. for their kind and valuable advice on our experiments, and all members of the Maekawa lab at Kyoto University Hospital for discussions of the data. This work was supported by JSPS KAKENHI Grant Numbers 25461415 (HH), 25430149 (AY) and 16K07171 (TM).

Author contributions

AY and HH designed and performed the experiments, analyzed the data and wrote the manuscript; TS performed the experiments; TM supervised the project; and KO designed and supervised the project and wrote the manuscript.

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Authors and Affiliations

  1. Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan

    A Yokota, H Hirai, T Shoji & T Maekawa

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

    K Okuda

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  1. A Yokota
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Correspondence to H Hirai or K Okuda.

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Yokota, A., Hirai, H., Shoji, T. et al. Constitutively active ABL family kinases, TEL/ABL and TEL/ARG, harbor distinct leukemogenic activities in vivo. Leukemia 31, 2742–2751 (2017). https://doi.org/10.1038/leu.2017.114

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