Failure of DNA repair mechanism precedes final stage of deadly leukemia, new Penn study shows

03/15/04

Preventing BCR/ABL oncogene from blocking normal DNA repair may allow patients with chronic myelogenous leukemia to live longer

(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 turned "on" and "off." DNA damage was linked to the protein ATR and measured using comet assays.

"If blocking DNA repair proves to be the cause of blast crisis, then we may be able to prevent CML from progressing to its final stage by interrupting the action of cancer gene BCR/ABL," said Carroll. "Ultimately, this could lead to a long-term treatment for the disease that may also be applied to other progressive cancers."

Funding for the study was provided through grants from Penn's School of Medicine and the National Cancer Institute (NCI). Started in January 1999, the study will continue through 2004 to determine the causal nature, if any, between BCR/ABL and blast crisis.

CML is a fatal blood cancer that primarily affects people over age 40. There are approximately 5,000 new cases each year in the United States, and nearly 2,000 people die from the disease. During the first stage of the illness, people live for three to five years after diagnosis. On average, people live for only three months to one year after entering the final, second stage of the disease.

Source: Eurekalert & others

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