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Leukaemia disease genes: large-scale cloning and pathway predictions

Nature Genetics volume 23, pages 348–353 (1999)Cite this article

Abstract

Retroviral insertional mutagenesis in BXH2 and AKXD recombinant inbred mice induces a high incidence of myeloid or B- and T-cell leukaemia1,2 and the proviral integration sites in the leukaemias provide powerful genetic tags for disease gene identification. Some of the disease genes identified by proviral tagging are also associated with human disease3,4,5, validating this approach for human disease gene identification. Although many leukaemia disease genes have been identified over the years, many more remain to be cloned6. Here we describe an inverse PCR (IPCR) method for proviral tagging that makes use of automated DNA sequencing and the genetic tools provided by the Mouse Genome Project, which increases the throughput for disease gene identification. We also use this IPCR method to clone and analyse more than 400 proviral integration sites from AKXD and BXH2 leukaemias and, in the process, identify more than 90 candidate disease genes. Some of these genes function in pathways already implicated in leukaemia, whereas others are likely to define new disease pathways. Our studies underscore the power of the mouse as a tool for gene discovery and functional genomics.

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Figure 1: Schematic representation of the IPCR proviral tagging method.

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Acknowledgements

We thank N. O'Sullivan for technical assistance; D. Gilbert for help with the IB mapping; and H.C. Morse and M.C. Dean for helpful comments. This research was sponsored in part by the National Cancer Institute, DHHS, under contract with ABL.

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Author notes

  1. Jiayin Li and Haifa Shen: These authors contributed equally to this work.

Authors and Affiliations

  1. Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Jiayin Li, Haifa Shen, Nancy A. Jenkins & Neal G. Copeland

  2. Department of Genetics, Cell Biology and Development, University of Minnesota Cancer Center, Minneapolis, Minnesota, USA

    Karen L. Himmel, Adam J. Dupuy & David A. Largaespada

  3. PRESTO, JST and Japanese Foundation for Cancer Research, Tokyo, Japan

    Takuro Nakamura

  4. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

    John D. Shaughnessy Jr

Authors
  1. Jiayin Li
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Correspondence to Neal G. Copeland.

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Li, J., Shen, H., Himmel, K. et al. Leukaemia disease genes: large-scale cloning and pathway predictions. Nat Genet 23, 348–353 (1999). https://doi.org/10.1038/15531

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