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Development of megakaryoblastic leukaemia in Runx1-Evi1 knock-in chimaeric mouse

Leukemia volume 20, pages 1458–1460 (2006)Cite this article

Chromosomal translocations involving the Runx1 gene create various chimaeric proteins that are believed to cause human leukaemia. Runx1-ETO and Runx1-Evi1, generated as consequences of t(8;21) and t(3;21), respectively, share molecular structural similarities; they both contain DNA-binding domain of Runx1 and transcriptional repression domains from either ETO or Evi1. Despite such similarity, the subtypes of leukaemia related to each of the chimaeric protein are different; Runx1-ETO typically occurs with acute myelocytic leukaemia of M2 subtype in the French–American–British classification, whereas Runx1-Evi1 is mostly associated with megakaryoblastic leukaemia of M7 subtype or megakaryoblastic crisis in chronic myelocytic leukaemia. Experimental animals that express the fusion proteins in the hematopoietic cells have been created to recapitulate the diseases. Both Runx1-ETO transgenic1 and conditional knock-in2 mice do not develop leukaemia by itself and require additional genetic aberrations to transform myeloid progenitors. Here, we report the development of megakaryoblastic leukaemia in Runx1-Evi1 knock-in chimaeric mouse.

The key aspect of our observation is that Runx1-Evi1 protein is leukaemogenic per se, unlike Runx1-ETO. Such clear difference in the pathophysiological outcome likely arises from the Evi1 portion of Runx1-Evi1 protein. Evi1 is reported to stimulate activator protein 1 activity,5 repress transforming growth factor-β signaling,6 and inhibit c-Jun N-terminal kinase function.7 Such versatile function of Evi1 may underlie stronger oncogenic capacity of Runx1-Evi1 than Runx1-ETO. Another important aspect is that the affected lineage in human is conserved in the experimental animal. Our observation indicates strong causal relationship between the expression of Runx1-Evi1 protein and megakaryoblastic leukaemia. Indeed, the Runx1-Evi1 chimaeric gene was isolated from a patient developing megakaryoblastic crisis in chronic myelocytic leukaemia that accompanied emergence of t(3;21).8 It is unknown whether Runx1-Evi1 is preferentially oncogenic in megakaryoblast, or show exclusive maturation block in the megakaryocytic lineage when expressed in early haematopoietic cells. Foetal liver cells from Runx1-Evi1 knock-in heterozygous embryo can give rise to dysplastic megakaryocytes.4 Such abnormal progenitors may have persisted in the adult bone marrow and expanded to cause massive infiltration of the megakaryoblasts in the liver and spleen.

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Acknowledgements

This work was supported by Grants-in-Aid from the Ministries in Japan of Education, Culture, Sports, Science and Technology, and Health, Labour and Welfare, and Japanese Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Haematology, Dokkyo Medical University School of Medicine, Tochigi, Japan

    K Maki, T Yamagata & K Mitani

  2. Department of Clinical Laboratory and Pathology, Inoue Memorial Hospital, Chiba, Japan

    I Yamazaki

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

    H Oda

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Correspondence to K Maki.

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Maki, K., Yamagata, T., Yamazaki, I. et al. Development of megakaryoblastic leukaemia in Runx1-Evi1 knock-in chimaeric mouse. Leukemia 20, 1458–1460 (2006). https://doi.org/10.1038/sj.leu.2404281

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