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Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice

Oncogene volume 27, pages 3465–3474 (2008)Cite this article

Abstract

Chronic myelogenous leukemia (CML) is a hematopoietic disorder, which begins as indolent chronic phase but inevitably progresses to fatal blast crisis. p210BCR/ABL, a constitutively active tyrosine kinase, is responsible for disease initiation but molecular mechanism(s) underlying disease evolution remains largely unknown. To explore this process, we employed retroviral insertional mutagenesis to CML-exhibiting p210BCR/ABL transgenic mice (Tg). Virus infection induced acute lymphoblastic leukemia (ALL) in p210BCR/ABL Tg with a higher frequency and in a shorter latency than wild-type littermates, and inverse PCR detected two retrovirus common integration sites (CISs) in p210BCR/ABL Tg tumors. Interestingly, one CIS was the transgene itself, where retrovirus integrations induced upregulation of p210BCR/ABL and production of truncated BCR/ABL with an enhanced kinase activity. Another CIS was Notch1 gene, where retrovirus integrations resulted in overexpression of Notch1 and generation of Notch1 lacking the C-terminal region (Notch1ΔC) associated with stable expression of its activated product, C-terminal-truncated Notch intracellular domain (NICDΔC). In addition, generation of Tg for both p210BCR/ABL and Notch1ΔC developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1ΔC/NICDΔC with p210BCR/ABL involving Stat5-mediated pathway. These results demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induces acute leukemia in a transgenic model for CML.

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Acknowledgements

We thank Yuki Sakai, Kayoko Hashimoto, Yuko Tsukawaki for mouse care and technical assistance and Shigeru Chiba and Ryuichi Sakai for providing us with mouse Notch1 cDNA and anti-phosphotyrosine antibody. This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (13-2), Research Grant of the Princess Takamatsu Cancer Research Fund, Mitsubishi Pharma Research Foundation, YASUDA Medical Research Foundation, a Grant-in-Aid of The Japan Medical Association and Japan Leukaemia Research Fund.

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Authors and Affiliations

  1. Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    T Mizuno, N Yamasaki, K Miyazaki, T Tazaki & H Honda

  2. Department of Orthopedic Surgery, Hiroshima University School of Medicine, Hiroshima University, Hiroshima, Japan

    T Mizuno & M Ochi

  3. Leukemogenesis Section, Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, MD, USA

    R Koller & L Wolff

  4. Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan

    H Oda

  5. Department of Allergy and Rheumatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Z-i Honda

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  1. T Mizuno
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Correspondence to H Honda.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mizuno, T., Yamasaki, N., Miyazaki, K. et al. Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice. Oncogene 27, 3465–3474 (2008). https://doi.org/10.1038/sj.onc.1211007

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