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Leukemia Genetic Signature, Drug Candidates Identified

DNA strand (Genome.gov)

(Genome.gov)

Researchers at University of Rochester in New York identified a set of genes behind the early growth of leukemia stem cells, and used those cells to highlight potential existing drugs with the chemistry to target those cells. The team led by senior investigator and Rochester medical school professor Craig Jordan — with colleagues from Weill Cornell Medical College in New York, Broad Institute of Harvard and MIT, and Brigham and Women’s Hospital in Boston — published its findings this month in the journal Cell Stem Cell (paid subscription required).

Leukemia stem cells are believed to be the first cells at the root of malignancy and renew uncontrollably. In earlier work, Jordan documented the aberrant behavior of these cells, building on research by collaborators at Rochester that cancer evolves from an interactive network of genes governed by their own rules. The colleagues, Hartmut Land and Helene McMurray, called these networks cooperation response genes, and noted their ability to influence primitive cancer cells in ways that dictate the patterns they form and the extent to which cancer progresses or stops.

Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the bloodstream. The disease is difficult to treat, and as noted in Jordan’s earlier paper, conventional chemotherapy is not always effective against leukemia because the treatments destroy both the leukemia and normal stem cells. In addition, conventional therapies often do not address the biologically distinct stem cells, allowing residual cancer to continue circulating in the blood stream.

The research team investigated human leukemia cancer cells and found some 70 cooperation response genes that influence the growth and survival of both primitive leukemia stem cells and more mature leukemia cells. In tests on mice, Jordan and colleagues knocked out the expression of these cooperation response genes and, as a result, reduced the growth of leukemia.

The researchers then submitted this genetic signature to the Connectivity Map at the Broad Institute. The Connectivity Map is a computational genomics tool that links gene patterns associated with disease to corresponding patterns produced by drug candidates and a variety of genetic manipulations. The computational features make it possible to screen compounds against genome-wide disease signatures, and thus pair drugs with diseases with a high level of specificity.

Using the signature from the leukemia stem cell cooperation response genes, the Connectivity Map identified two candidates as potential treatments: a drug in development (but not yet approved) for breast cancer and an experimental drug that had already been identified as an agent that targets leukemia cells.

While these early matches still need further review and testing, Jordan believes the research so far has given investigators a powerful new set of tools. “We were able to use the latest technology to expand very strong basic laboratory concepts,” says Jordan, “and conduct an intriguing analysis that may yield new insights for treatments of leukemia.”

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