Candidate Leukemia Drugs Target Activity of Cooperation Response Genes

Cancer researchers have identified a set of genes that operate in a cooperative fashion to regulate the growth and survival of leukemia stem cells (LSCs), a biologically distinct subpopulation of myeloid leukemias with reduced cell cycle activity and increased resistance to chemotherapy.

Leukemia is known for being particularly resistant to treatment. In part, this resistance is due to the LRC population that remains unaffected by chemotherapy and provides a source of new cancer cells that cause relapse of the disease following treatment.

Investigators at the University of Rochester (New York, USA) used both a primary mouse model and human leukemia specimens to study the genes that control LRC growth and survival. To this end they adapted an approach based on identification of genes synergistically dysregulated by cooperating oncogenes. This class of genes - similar to a pool of approximately 100 genes that was found to cooperate to promote colon cancer - had been nicknamed “cooperation response genes” (CRGs).

Results published in the August 2, 2012, online edition of the journal Cell Stem Cell revealed that approximately 70 CRGs played a role in growth and survival of both primitive leukemia cells and more mature leukemia cells. Silencing the expression of these CRGs in the mice model reduced leukemia growth.

The investigators screened hundreds of known drug compounds for the ability to disrupt leukemia CRG activity. Two compounds were identified and are now being evaluated as possible drug candidates.

“No one else has used the targeting of CRGs as criteria to look for drugs that might treat cancer,” said senior author Dr. Craig T. Jordan, professor of medicine at the University of Rochester. “By using the CRG approach, we found drug compounds that might never have been selected, based on their documented mechanism of action. Our work is both basic and translational, and is an example of a terrific collaboration. We were able to use the latest technology to expand very strong basic laboratory concepts and conduct an intriguing analysis that may yield new insights for treatments of leukemia.”

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