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Targeting errant immune system enzyme kills myelodysplastic cells
Date:7/8/2013

rom past studies that analyzed elevated gene expression in MDS cases and then conducted their own analyses of MDS and AML patient cells. The research team verified that an immune system enzyme called IRAK1 (Interleukin Receptor Associated Kinase-1) is highly over-expressed and hyper-activated in about 25 percent of MDS/AML cells.

The researchers then tested the effect of blocking IRAK1 on human MDS cells, on mouse models of human MDS and on normal human CD34+ blood cells. They used both direct genetic inhibition and a small-molecule inhibitor of IRAK1 (called IRAK-Inh) that was developed initially as prospective treatment for autoimmune disease and chronic inflammation.

Both genetic and pharmacologic inhibition of IRAK1 was effective at slowing the progression of human MDS cells and in mouse models of the disease. Inhibiting IRAK1 also had no effect on normal human CD34+ blood cells, showing it selectively targets MDS cells.

A possible shortcoming to IRAK-Inh treatment was discovered when researchers noticed it was not effective at overcoming a pro-cancer survival gene called BCL2. In some cell lines treated with IRAK-Inh, BCL2 genes became overexpressed in an effort to compensate for and work around the experimental treatment a common occurrence in certain cancer therapies.

Researchers responded by testing a collaborative treatment strategy, combining IRAK-Inh with an inhibitor of BCL2 called ABT-263. The combination treatment was effective at selectively targeting and killing MDS cells without harming normal blood cells.

Starczynowski cautioned that laboratory tests in mouse models and cell cultures do not necessarily translate into treatment for humans. Because IRAK1 is currently thought to be overexpressed in a subset of MDS patients, any prospective drugs targeting the enzyme would in theory benefit only that group.


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Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

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