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Animal Models

Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis

Leukemia volume 26, pages 1038–1045 (2012)Cite this article

Abstract

Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was frequently observed in human T-cell malignancies. In a mouse bone marrow transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth factor withdrawal or phorbol ester stimulation than those transduced with RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 mutations resulting in a gain of function were found in 77% of the RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 mutation was found in human T-cell malignancy with elevated expression of RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 was attenuated by the disruption of a protein kinase C phosphorylation site (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.

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Acknowledgements

We thank Dr Shigeru Chiba for kindly providing plasmids. This work was supported by the Ministry of Education, Science, Technology, Sports and Culture, Japan.

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Authors and Affiliations

  1. Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    T Oki, J Kitaura, N Watanabe-Okochi, K Nishimura, A Maehara, T Uchida, Y Komeno, F Nakahara & T Kitamura

  2. Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    T Oki & T Kitamura

  3. Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    N Watanabe-Okochi

  4. Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Y Harada

  5. Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan

    T Sonoki

  6. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    H Harada

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Correspondence to T Kitamura.

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TK serves as a consultant for R&D Systems. The other authors declare no conflict of interest.

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Oki, T., Kitaura, J., Watanabe-Okochi, N. et al. Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis. Leukemia 26, 1038–1045 (2012). https://doi.org/10.1038/leu.2011.328

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