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AML1 deletion in adult mice causes splenomegaly and lymphomas

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Abstract

AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective T-lymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.

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Acknowledgements

We thank Roland Naumann, Maxi Oelsner, Sigrid Balschukat, Irena Konstantinova, and the Department of Internal Medicine I of the Carl Gustav Carus University Hospital Dresden for providing technical assistance, Jussi Helppi, Anke Muench-Wuttke, and Anja Klieman for biomedical services. Thanks also to Ralf Kittler, Carol Stocking and Joerg Cammenga for scientific discussion. We are grateful to Dennis Corbeil for providing us with the Prominin-1 antibody. This study was supported by the Max Planck Society, the Deutsche José Carreras Leukaemie-Stiftung e.V., and the Deutsche Forschungsgemeinschaft (SFB 655 and BA1433/4-2).

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Authors and Affiliations

  1. Max-Planck-Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse, Dresden, Germany

    G Putz, I Nuesslein, N Schmitz & F Buchholz

  2. Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Experimentelles Zentrum, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr., Dresden, Germany

    A Rosner

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  1. G Putz
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  2. A Rosner
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  3. I Nuesslein
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  4. N Schmitz
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  5. F Buchholz
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Correspondence to F Buchholz.

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

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Putz, G., Rosner, A., Nuesslein, I. et al. AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene 25, 929–939 (2006). https://doi.org/10.1038/sj.onc.1209136

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