International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F6 Modeling Cancer in the Mouse: Rapid Proviral Tagging of Novel Proto-Oncogenes Responsible for the Development of B-Cell Leukemia

Monica J. Justice, Gwenn M. Hansen, Darlene Skapura, and Alex George. Dept. of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77096

Retroviruses can cause cancer in mice by integrating near and altering the expression of cellular proto-oncogenes. AKXD recombinant inbred strains of mice develop leukemias and lymphomas as a result of the somatic integration of murine leukemia retroviruses (MuLVs). MuLV sequences can be used as molecular tags to identify and clone genes associated with lymphoma development. Many of the AKXD strains predispose to B-cell disease; thus, the AKXD mice are valuable for understanding the molecular genetic basis for the development of B-lineage leukemias and lymphomas. A new viable AKXD B-cell tumor bank has been generated by aging strains that are susceptible to B-cell disease. A PCR technique called viral insertion site amplification (VISA) was developed to quickly identify all of the genes near somatic proviral insertions in this leukemia subset. Using VISA, we have identified multiple common insertion sites that represent known proto-oncogenes, known genes previously not implicated in tumorigenesis, and unknown sequences.

Proviral insertions at one site, called Lvis1, occur in 22% of the B-lineage leukemias and lymphomas, and thus Lvis1 represents the most frequently altered locus in the AKXD mice1. We have identified two genes that are misexpressed at Lvis1: the orphan homeobox gene, Hex, and a kinesin-related spindle protein, Eg5. Preliminary studies suggest that Hex plays a primary role in the development of mouse B-cell leukemia, and may also be involved in human leukemia. Hex acts as a transcriptional repressor, and thus may be involved in repressing lineage inappropriate genes, or genes involved in terminal differentiation or lymphocyte activation.

Our data and tumor resources from the AKXD mice are important cancer genomics tools: 1) the insertion sites represent biologically relevant regions of the mouse genome for which sequence identification is important, 2) their identification can be correlated with large-scale gene expression data from mouse and human tumors, and 3) the tumor archive represents a viable resource of tumor cells for biological studies. A complete compilation of the genes disrupted by viral insertion, along with the biological resources necessary to study them in detail will further our understanding of cancer development and susceptibility in these strains and in human disease.

1Hansen, G. M. and Justice, M. J. Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia. Oncogene, In press.


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