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Reversibility of acute B-cell leukaemia induced by BCR–ABL1

Nature Genetics volume 24, pages 57–60 (2000)Cite this article

Abstract

Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukaemias initiated by a chromosomal translocation. We have taken a new approach to determine if ablation of the genetic abnormality is sufficient for reversion by generating a conditional transgenic model of BCR–ABL1 (also known as BCR–ABL)-induced leukaemia. This oncogene1 is the result of a reciprocal translocation and is associated with different forms of leukaemia2. The most common form, p210 BCR–ABL1, is found in more than 90% of patients with chronic myelogenous leukaemia3,4 (CML) and in up to 15% of adult patients with de novoacute lymphoblastic leukaemia5 (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis6,7, by reduced penetrance or by extremely long latency periods8,9. One model uses the ‘knock-in’ approach to induce leukaemia by p190 BCR–ABL1(ref. 10). Given the limitations of models with p210, we used a different experimental approach11. Lethal leukaemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR–ABL1expression, even after multiple rounds of induction and reversion. Our results demonstrate that BCR–ABL1is required for both induction and maintenance of leukaemia.

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Figure 1: Induction of leukaemia by BCR–ABL1 under the control of the ‘tet-off’ system in transgenic mice.
Figure 2: Expression of BCR–ABL1 induces an acute pre-B cell leukaemia.
Figure 3: Analysis of immunoglobulin rearrangements and p210 protein expression in mice from different founder lines with B-cell ALL.
Figure 4: The leukaemic phenotype is reversibly dependent on the continuous expression of BCR–ABL1.
Figure 5: Apoptosis of leukaemic cells in peripheral blood following re-administration of tetracycline.

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Acknowledgements

We thank M. Fenyus for assistance in animal care; L. Hennighausen for providing the MMTV-tTA strain; J. Lawitts of the BIDMC transgenic facility for expert rederivation and generation of transgenic lines; S. Takamatsu for assistance with photography; M. Singleton for assistance with preparation of the manuscript; and J.D. Griffin, G. Gilliland, D.-E. Zhang, K.P. Lu, C. Carpenter and L.K. Clayton for useful discussions. This work was supported by grants from the NIH to D.G.T., research grants from the NIH and the Leukemia Society of America to R.A.V. and from the Deutsche Forschungsgemeinschaft to C.S.H.

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Authors and Affiliations

  1. Hematology/Oncology Division, Harvard Institutes of Medicine and Harvard Medical School, Boston, Massachusetts, USA

    Claudia S. Huettner, Pu Zhang & Daniel G. Tenen

  2. Center for Blood Research, Harvard Medical School, Boston, Massachusetts, USA

    Richard A. Van Etten

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  1. Claudia S. Huettner
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  2. Pu Zhang
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Correspondence to Daniel G. Tenen.

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Huettner, C., Zhang, P., Van Etten, R. et al. Reversibility of acute B-cell leukaemia induced by BCR–ABL1. Nat Genet 24, 57–60 (2000). https://doi.org/10.1038/71691

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