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DNA Methylation May Explain Some Types Of Lymphoma

Researchers have discovered a unique gene modification in adult human cancer cells that could provide insight into the cause of certain types of lymphoma and possibly other cancers.

This is the report from UCLA's Jonsson Cancer Center in an article published Tuesday in the Proceedings of the National Academy of Sciences (PNAS).

This initial basic science discovery could lead to others that may, in time, allow for new treatments to specifically target these types of lymphoma, said Dr. Mike Teitell, a physician and researcher at UCLA's Jonsson Cancer Center and the lead author of the article.

As part of ongoing cancer research, Teitell and UCLA scientists Randolph Wall, Steven Jacobsen, Cindy Malone and their colleagues were investigating how people with AIDS -- because of their severely depressed immune systems -- develop certain types of lymphoma, hoping they could pinpoint potential causes of the disease.

In one type of lymphoma developed by AIDS patients, called primary effusion lymphoma (PEL), Teitell and his team observed that many of the cells' normal genes had been silenced, or turned off. It's not unusual for genes to be silenced in cancer, and, in fact, silenced genes may be the cause of cancer in some cases, Teitell said.

Given that, he and his scientific team set out to discover why the genes were silenced in AIDS-related primary effusion lymphoma cases.

In looking at one of the genes that had been silenced, called B29, Teitell and his team found a new kind of gene modification, one seen before only in early mammalian stem cells and in plants and bacteria.

The modification, a type of DNA methylation, could be a cause of this type of lymphoma, although more research is necessary to confirm that, Teitell said.

"One implication of this finding is that cancers that revert to earlier stages of development may be using this new type of DNA modification to accomplish this reversion," Teitell said. "The cancer cells stop utilizing the genes for differentiation that normal cells utilize and instead use genes that cause the cells to keep dividing unchecked.

"If we could understand how and why this type of DNA methylation is occurring, and what enzymes are involved, we might understand more fully how this lymphoma originates."

In this modification, methyl (CH3) groups are added to the DNA of specific genes within the cell at specific sites. These groups sit on the DNA and block certain proteins from binding. In this way, the DNA methylation could be stopping the cell from operating normally, Teitell said.

"By silencing cellular genes, this type of modification is damaging a cell's ability to sense its environment and may be causing it to grow uncontrollably," Teitell said.

Teitell called the discovery of this type of gene modification "quite unexpected," and potentially significant.

"It suggests that the cancer uses this modification to revert back to an earlier stage of development, to spend all its time utilizing genes that allow mainly for growth," Teitell said.

In further research, Teitell and his team found the same type of gene modification in a multiple myeloma cell line. That leads researchers to question whether this type of gene modification goes beyond the specific AIDS-related lymphomas found in this research.

"This could be a general phenomena found in more than one form of cancer," Teitell said. "It may be that this modification is a piece of the mechanism that causes a cell to become cancerous. One thing that is not yet known is what enzyme causes this type of DNA methylation. Once we know that, and we're looking into it, we may be able to develop strategies to block it."

Teitell and his team are working now to discover what enzyme is involved in the DNA methylation and how common this specific type of gene silencing is in other cancers.

The discovery of the new gene modification was the result of more than a year of laboratory research. If this modification is linked to the development of cancer, it could be targeted to potentially stop the disease, Teitell said.

In the same issue of PNAS, researchers Matthew C. Lorincz and Mark Groudine from the Fred Hutchinson Cancer Research Center in Seattle wrote a review of Teitell's article, indicating that their discovery of this new pattern of DNA modification may be important in gene regulation in both normal and cancerous cells.

Related websites:

Proceedings of the National Academy of Science

UCLA's Jonsson Cancer Center

[Contact: Kim Irwin, Kambra McConnel]






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