(Philadelphia, PA) Medical researchers at the Abramson Cancer Center of the University of Pennsylvania have discovered that the last stage of chronic myelogenous leukemia (CML), a deadly blood cancer, is preceded by the unique blocking action of a blood cell's normal cycle of DNA production and repair. The researchers linked the blocking action to a known oncogene, BCR/ABL, and suspect it to be the cause of blast crisis, the second and final stage of CML disease when the body no longer makes enough healthy white blood cells to fight off infection or prevent bleeding. Their findings appear in the March 23rd edition of the journal Cancer Cell.

"The BCR/ABL oncogene is known to play a direct role in the first, non-deadly stage of CML, where over-production of white cells occurs and can be treated for a limited time by medication," said lead author Martin Carroll, MD, an Assistant Professor of Medicine at Penn's School of Medicine. "Now we know that BCR/ABL also disrupts the cell's ability to repair itself, blocking a protein called ATR that regulates normal DNA synthesis. This leads to an accumulation of genetic mutations, or mistakes which immediately precedes the final, incurable stage of CML."

It can take up to a year for a patient to transition from the first phase of CML to blast crisis. In this deadly, blast crisis phase of CML, new white blood cells fail to mature into fully-functioning cells and, instead, become myeloblasts in a state of arrested differentiation. In order to block ATR and DNA repair, cancer researchers also found that the concentration of BCR/ABL moves into the nucleus of the cell where DNA is produced from its original concentration in the cell's cytoplasm. Further research is planned to determine if this movement of BCR/ABL is a trigger or effect of blast crisis.

Researchers were able to determine the workings of BCR/ABL by comparing the amounts of damaged to un-damaged DNA in a cell line when the oncogene was
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Contact: David March
david.march@uphs.upenn.edu
215-615-3353
University of Pennsylvania School of Medicine
22-Mar-2004

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