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Lab is focused on the molecular mechanisms causing human lymphoid
malignancies. Many of the abnormalities in lymphomas, leukemias
and multiple myeloma involve genes that also regulate normal
lymphoid development. In particular, we are interested in
the normal development of germinal center B cells since many
of the non-Hodgkin's lymphomas are derived from cells that
have passed through this developmental stage.
tool in the lab is genome-wide DNA microarray analysis of
gene expression which is capable of quantitating the express
of tens of thousands of genes in parallel. We use this techn
to view the gene expression profiles of distinct stages of
lymphoid development and compare these to the gene expressio
profiles of human lymphoid malignancies. This approach will
ultimately provide a new molecular classification of these
cancers. Current efforts are directly towards all types of
non-Hodgkin's lymphomas, chronic lymphocytic leukemia, and multiple myeloma.
A new initiative in our laboratory aims to identify additional molecular targets in lymphoid malignancies using large scale RNA interference. Specifically, the laboratory is using retroviruses to express small hairpin RNAs (shRNAs) in cancer cells in an inducible fashion. Our laboratory has created a library of 7,500 retroviruses that can express shRNAs targeting 2,500 genes. Each shRNA is associated with a unique 60-nucleotide "bar code" sequence, which allows the abundance of each shRNA to be monitored in a cell population using DNA microarrays of the bar code sequences. One current application of this shRNA library is to identify genes important for the proliferation and survival of lymphoma cells. A cancer cell line is infected with a library of shRNA-expressing retroviruses such that each individual cancer cell expresses only one shRNA on average. As the population of cancer cells grows in vitro, those cells with shRNAs targeting genes critical for proliferation or survival will be selectively eliminated from the population, which can be measured using a DNA bar code microarray. We have found that this high throughput functional genomics screen can identify potential new therapeutic targets in lymphoma and multiple myeloma that include components of the NF-kB pathway. More generally, this methodology can extend the realm of molecular targets in cancer beyond oncogenes and tumor suppressor pathways.
our current projects here.
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