Mouse cancer genetics

Our laboratory is interested in studying cancer and mouse development. We use a range of genetic, genomic and biochemical approaches in the lab and develop novel technologies to facilitate our studies.

Cancer is a genetic disease caused by mutations at multiple genetic loci. These genetic changes make cancer cells switch developmental fates, escape immuno-surveillance, and become metastatic. Identification of the mutations in oncogenes and tumour suppressors and elucidation of their functions in normal development should lead to a better understanding of the basic biological mechanisms of the disease process and also facilitate the rational development of new and effective therapies.

[Wellcome Library, London]

Background

Laboratory mice have traditionally been used as the animal model of choice for studying human cancer. Mice and humans are similar in many aspects of their biology including their anatomy, physiology, metabolism, cellular signal transduction, and genome. Additionally laboratory mice have a short reproductive cycle and relatively large litter sizes. These features make it possible to generate inbred mouse strains, with each possessing an identical genetic background. In particular, some inbred mouse strains have a high incidence of cancer. For example, C3H mice develop mammary tumours, and BXH2 and AKXD mice have a high incidence of leukaemia. In these cases retroviral insertions are the mutagens that cause tumour development. The completion of the Human Genome Project, and the availability of the mouse genome sequence, will greatly facilitate the identification of genes mutated in these tumours. So far over 160 mutated genes have been found in AKXD and BXH2 tumours in the laboratory of Dr Neal Copeland and Dr Nancy Jenkins at the National Cancer Institute, USA. Many of these genes are known oncogenes in human cancers and some of them have since been identified as mutated in human tumours, thus validating the value of the mouse as the model for human cancer.

Figure 1. Bcl11a is essential for lymphocyte development.

Figure 1. Bcl11a is essential for lymphocyte development.

zoom

Research

At the Wellcome Trust Sanger Institute, and in collaboration with Dr Neal Copeland and Dr Nancy Jenkins, we will perform a systematic screen to identify genes mutated in AKXD tumours. We will utilise the sequencing and bioinformatics capacity at the Sanger Institute, and develop innovative technologies for comprehensive screening of genes mutated in the tumours. Cloning of a large number of putative oncogenes and tumour suppressor genes will enable us to develop a rational database to delineate the genetic pathways, or signal transduction pathways, required for the tumour development. Some of the genes isolated from this screen will be further analysed for their roles in normal development and in cancer.

We have previously analysed Bcl11a (Evi9), which was originally identified as a gene activated by retroviral insertion in BXH2 and AKXD tumours. We found that Bcl11a is essential for B-cell lineage formation and for normal T-cell development. Interestingly, deficiency of Bcl11a also led to T-cell leukaemia in foetal-liver cell transplantation experiments. BCL11A was later found to be involved in chromosomal translocations in human B-cell lymphoma patients. Therefore Bcl11a is essential for lymphocyte development and can act as an oncogene or a tumour suppressor gene, depending on the cellular contexts. One project in the laboratory will be to study the roles of Bcl11a and Bcl11b (Bcl11a related gene) in lymphocyte development and maturation, in immune responses, in signal transduction, and in tumour development.

In addition to studying leukaemia genes in the mouse we will also develop new ways to identify and to characterise genes that are causally involved in other types of tumours in the mouse.

Recombineering and conditional knockouts

The mouse is unique amongst mammals in the extent to which its genome is amenable to genetic manipulation. Production of gene knockout and gene overexpression mice is now a routine task in genetics laboratories. In the last few years a highly efficient approach to manipulate DNA in E.coli has become available. This technology, termed recombineering, utilises the homologous recombination system from bacteria phage lambda. Various DNA manipulations can be achieved in E.coli by transiently activating the phage recombination system. We will develop a procedure to construct conditional knockout targeting vectors for many mouse genes. Of particular interest is that our alleles will detect the endogenous gene expression patterns, can be used to conditionally activate the genes in specific cells and also allow detection of mutant cells from wild type cells after Cre-loxP induced recombination.

Cre-loxP-induced mitotic recombination in the mouse

We have shown that Cre-loxP can mediate efficient mitotic recombination in mouse ES cells. The recombination frequencies vary among different genetic loci in the genome. This project will:

  1. identify additional genetic loci that allow high mitotic recombination frequencies in mouse ES cells;
  2. identify the in vivo recombination frequencies in the mouse;
  3. perform chromosome specific genetic screens using the mitotic recombination systems developed.

Selected Publications

  • Reprogramming to Pluripotency Using Designer TALE Transcription Factors Targeting Enhancers.

    Gao X, Yang J, Tsang JC, Ooi J, Wu D and Liu P

    Stem cell reports 2013;1;2;183-97

  • Bcl11a is essential for lymphoid development and negatively regulates p53.

    Yu Y, Wang J, Khaled W, Burke S, Li P, Chen X, Yang W, Jenkins NA, Copeland NG, Zhang S and Liu P

    The Journal of experimental medicine 2012;209;13;2467-83

  • Bcl11a is essential for normal lymphoid development.

    Liu P, Keller JR, Ortiz M, Tessarollo L, Rachel RA, Nakamura T, Jenkins NA and Copeland NG

    Nature immunology 2003;4;6;525-32

  • Evi3, a common retroviral integration site in murine B-cell lymphoma, encodes an EBFAZ-related Krüppel-like zinc finger protein.

    Warming S, Liu P, Suzuki T, Akagi K, Lindtner S, Pavlakis GN, Jenkins NA and Copeland NG

    Blood 2003;101;5;1934-40

  • A highly efficient recombineering-based method for generating conditional knockout mutations.

    Liu P, Jenkins NA and Copeland NG

    Genome research 2003;13;3;476-84

  • Efficient Cre-loxP-induced mitotic recombination in mouse embryonic stem cells.

    Liu P, Jenkins NA and Copeland NG

    Nature genetics 2002;30;1;66-72

  • Requirement for Wnt3 in vertebrate axis formation.

    Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR and Bradley A

    Nature genetics 1999;22;4;361-5

  • Embryonic lethality and tumorigenesis caused by segmental aneuploidy on mouse chromosome 11.

    Liu P, Zhang H, McLellan A, Vogel H and Bradley A

    Genetics 1998;150;3;1155-68

  • Chromosome engineering in mice.

    Ramírez-Solis R, Liu P and Bradley A

    Nature 1995;378;6558;720-4

  • Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit.

    Pentao L, Wise CA, Chinault AC, Patel PI and Lupski JR

    Nature genetics 1992;2;4;292-300

Team

No team members listed

* quick link - http://q.sanger.ac.uk/mousecan