Chromosomal Abnormality : Scientists a Step Closer to Linking Leukemia, Genes

United Press International

Scientists have moved a significant step closer to confirming a link between a deadly form of leukemia and two specific genes, a finding that may enhance understanding of the critical role genes play in cancer development.

In a series of studies by an international team of researchers, investigations conclude that two insidious oncogenes, cancer-causing genes, are associated with acute lymphoblastic leukemia (ALL), a form of the disease that primarily strikes children and young adults.

Scientists from Childrens Hospital in Los Angeles, Erasmus University in the Netherlands and the Institute of Cancer Research in London reported their findings in a recent issue of Cell, a scientific journal.

Chromosomal Abnormality

The oncogenes apparently underlie formation of an unusual chromosomal abnormality that occurs when fragments of two chromosomes break and change places in a process called translocation.

The scientists report that mechanisms causing translocations in the development of leukemia are still being explored.

This study and earlier investigations have shown that the oncogenes become activated when they come together on one of the newly transformed chromosomes where an abnormal protein is produced as a result of their fusion.

The chromosome where this deadly chemical event occurs is known as the Philadelphia chromosome that was found in the lymphocytes of those affected by the disease. The Philadelphia chromosome for years has been associated with chronic myelogenous leukemia (CML), one of the more severe forms of the cancer that most frequently occurs in adults between the ages of 30 and 50.

The chromosome, so named because of its discovery at the Wistar Institute in Philadelphia in the 1960s, is one of the key markers for which doctors look to confirm a diagnosis of CML.

Now, the international team suggests that the chromosome may also be prominent in some patients suffering ALL.

"The Philadelphia chromosome is the best-known chromosomal abnormality related to cancer in human beings," said John Groffen chief of molecular genetics at Childrens Hospital and an associate professor of pediatrics and microbiology at the USC School of Medicine.

'30% of the Cases'

"In CML, this chromosome will be found all of the time," Groffen said. "But in ALL, it appears as if it is present in at least 30% of the cases."

Groffen said the presence of abnormal fusion proteins in ALL and CML Philadelphia chromosomes suggest the two leukemias may have a common molecular basis.

But despite the presence of the same oncogenes in the development of the two types of leukemia, different cells are affected and different lethal proteins are produced. CML primarily affects a type of white blood cell known as granulocytes, and in ALL the affected cells are the carriers of immunity known as lymphocytes, which also compose a portion of the white cells found in blood.

The molecular thread that links the two cancers, however, appears to be the process of translocation and the potential for a killer chemical machinery that can ensue when the two oncogenes fuse, Groffen said.

"The abl gene and the bcr gene come together to form a product that is abnormal in the cell. The abl oncogene is normally located on chromosome 9, and the bcr is normally located on chromosome 22."

He added that when chromosome 9 carrying abl becomes erroneously attached to chromosome 22, the result is a shorter chromosome 22 and a metamorphosis in the affected cells.

'Supersedes All Else'

"This causes a number of responses in the cell which throw off the entire regulation of the cell," Groffen explained. "So everything that occurs in the cell is dominated by the activity of the Philadelphia chromosome. Its activity supersedes all else."

Dr. Stuart Siegel, chief of hematology and oncology at Childrens Hospital, said, "It's important for physicians treating cancer patients to know whether or not these patients may have the Philadelphia chromosome."

"The prognosis for patients who have acute lymphoblastic leukemia and the Philadelphia chromosome is significantly poorer than for those who don't," said Siegel, who added that the median survival rate for ALL patients is one year.

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