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Drug resistant leukemia stem cells may be source of genetic chaos, Temple scientists find
Date:12/11/2012

(Philadelphia, PA) An international team of scientists, led by researchers from Temple University School of Medicine, has found that a source of mounting genomic chaos, or instability, common to chronic myeloid leukemia (CML) may lie in a pool of leukemia stem cells that are immune to treatment with potent targeted anticancer drugs. They have shown in mice with cancer that even after treatment with the highly effective imatinib (Gleevec), stem cells that become resistant to these drugs tyrosine kinase inhibitors (TKIs) may continue to foster DNA damage, potentially leading to disease relapse and a downward spiral to a much more deadly "blast" stage of leukemia.

Identifying a source of such genomic instability may help investigators eventually devise new treatment strategies against drug-resistant CML and other difficult-to-treat diseases.

"We showed that mice that mimic human CML are continuing to accumulate DNA damage despite treatment with imatinib," said senior investigator Tomasz Skorski, MD, PhD, Professor of Microbiology and Immunology at Temple University School of Medicine. "This implies that whether a patient with CML is being treated or not, DNA damage can continue to accumulate and can confer resistance and possibly lead to relapse in some patients." Dr. Skorski, first author Elisabeth Bolton Gillespie, a graduate PhD student in the Department of Microbiology and Immunology, and their co-workers presented their findings December 11 at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta.

In CML, an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML.

While treatment with imatinib is usually effective in control
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Contact: Steven Benowitz
steven.benowitz@tuhs.temple.edu
215-707-4784
Temple University Health System
Source:Eurekalert

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