Mouse model of human leukemia/lymphoma
It is estimated that more than 87,000 new cases of leukemia and non-Hodgkin’s lymphoma were diagnosed last year in the United States (Leukemia and Lymphoma Society). The pro-B cell malignancy that develops in Lig4 Trp53 double null mice recapitulates many features of human B-lineage lymphomas or leukemias, including chromosomal translocations involving immunoglobulin (Ig) loci and gross overall karyotypic complexity. Therefore, another important focus of the lab is the exploitation of this B-ALL mouse model to understand the molecular pathobiology of the human disease. Several different approaches are being employed.
Array CGH
It is well known that, like chromosomal translocations, gene deletion and gene amplification are common chromosomal abnormalities affecting tumor cells. Comparative genomic hybridization on an array of genomic clones (array CGH) is a powerful tool for identification of such copy number abnormalities. We are refining a high resolution array CGH platform to enable the precise identification of affected regions and their boundaries. By this approach we will be able to interrogate tumors with high sensitivity and resolution We hope to 1) define chromosomal deletion and amplification regions and identify the genes that reside in the affected intervals; and 2) accurately map gene deletion and amplification boundaries, to elucidate mechanistic aspects of copy number aberrations.
Gene expression profiling
While it is typical in B-ALL to find widespread dissemination in secondary lymphoid organs, the mechanism for this dissemination remains obscure. Lig4 Trp53 double null tumors are similar in this regard, typically locating to bone marrow, spleen, lymph nodes, and thymus. This is a highly aberrant situation, as progenitor B cells normally reside in the bone marrow, with very few entering circulation. To dissect the constellation of adaptive gene expression changes that allow transformed progenitor B cells in this model to home to ectopic locations, we are employing gene expression profile analysis, using two different platforms.
