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Activated K-Ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model

Leukemia volume 25, pages 888–891 (2011)Cite this article

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Acute lymphoblastic leukemia (ALL) with MLL/AF4 fusion is a common infant leukemia associated with a poor prognosis.1 Research into the molecular mechanisms underlying ALL with MLL/AF4 has been hampered by the absence of a good animal model. Recently, two murine MLL/AF4 models (knock-in and inverter models) were established, in which the MLL/AF4 allele caused a B-cell lymphoma after a mean latency of at least 14 months,2, 3 while another frequent MLL fusion, MLL/AF9 murine models developed in leukemia in a short latency (5–6 months).4 There is thus a substantial discrepancy between the late onset of disease seen in murine MLL/AF4 models and very early onset seen in human infants. Another novel murine MLL/AF4 model (human-derived AF4 knock-in model by using Cre/Lox approach) showed MLL/AF4 induces acute leukemia in a short latency.5 However, this model had a propensity toward acute myelogenous leukemia development, which differs from the strong association between MLL/AF4 and ALL in humans.

In an effort to develop a mouse model showing more aggressive oncogenesis, we have been focusing on Ras mutation as a factor that could explain discrepancy between murine model and human ALL with MLL/AF4. It is known, for example, that activating mutation of Ras gene and abnormalities in Ras signaling lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. In addition, Liang et al.6 reported that MLL-positive B-ALL is closely associated with Ras mutation (50%), especially with K-Ras mutation (40%), whereas MLL-positive acute myeloid leukemia is not. Therefore, we established MLL/AF4+K-Ras mutation+ Tg mice by crossing the newly established MLL/AF4+ Tg mice and K-Ras mutation+ Tg mice, which had an activated K-rasG12D.7 We then used these mice to determine whether the combination of K-Ras mutation and the MLL/AF4 fusion gene could produce the aggressive disease progression seen in cases of ALL with MLL/AF4 in humans.

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Acknowledgements

We thank Dr R Van Etten of Harvard Medical School for kindly providing pMSCVneop230 BCR/ABL plasmid. This work was supported in part by grants (No. 19591142) from the Ministry of Health and Welfare of Japan and the Ministry of Education, Science and Culture of Japan.

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  1. Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research Center for Advanced Medical Technology, Nippon Medical School, Tokyo, Japan

    H Tamai, K Miyake, N Miyake & T Shimada

  2. Department of Hematology, Nippon Medical School, Tokyo, Japan

    H Tamai, H Yamaguchi, K Dan & K Inokuchi

  3. Research Center for Life Science, Nippon Medical School, Tokyo, Japan

    M Takatori

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  1. H Tamai
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Correspondence to K Inokuchi.

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Tamai, H., Miyake, K., Takatori, M. et al. Activated K-Ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model. Leukemia 25, 888–891 (2011). https://doi.org/10.1038/leu.2011.15

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