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Master blood cell gene identified
Boston | Thursday, March 18, 2004, 08:00 Hrs  [IST]

A gene first identified as the cause of a rare but deadly form of leukemia turns out to play a master role in controlling the body's blood system, researchers at the Dana-Farber Cancer Institute report.

The discovery could lead to new ways of treating many forms of leukemia, says Dr. Stanley Korsmeyer, director of the Dana-Farber Program in Molecular Oncology and leader of the group reporting the finding in the March 16 issue of Developmental Cell.

The gene is called MLL, for mixed lineage leukemia, an aggressive form of blood cancer that affects a small number of infants and some adults who have relapsed after treatment for other leukemias.

"This cancer is an exaggeration of the normal role of this gene," says Korsmeyer. "It is too much of a good thing."

The good thing is production of blood cells. In MLL, the gene gets stuck in the "on" position because the chromosome on which it is located suffers a break at that specific site. The result is the uncontrolled proliferation of blood cells that is leukemia.

"We are one of about three people who have cloned that chromosomal breakpoint," Korsmeyer says.

Starting from there, the Dana-Farber researchers used embryonic stem cells first to create a line of cells lacking the MLL gene, then a strain of mice that did not have the gene. Stem cells are early forms that can develop into a variety of mature cells, depending on the genetic instructions they receive.

The studies showed the absence of the gene had profound effects on the hematopoietic system, which produces the red and white blood cells required for a living animal, Korsmeyer says. The MLL gene regulates the activity of a number of other genes whose activity produces blood cells, he says.

"This would place MLL with a handful of other genes, many involved in leukemia, that are required for the commitment of stem cells to form mature blood cells," Korsmeyer says. "This one is probably in a position that influences the way multiple lines of cells are formed."

In addition to adding significantly to knowledge about the genetics of the blood cell system, the finding could lead to new ways of treating leukemias, he says.

"One current fancy concerns an enzyme that helps activate MLL," Korsmeyer says. "It would be very attractive if we could inhibit the enzyme."

A more direct possibility would be to regulate the activity of MLL itself, he says.

Both lines of attack are being explored in the Dana-Farber laboratory. Panels of cancer cells will be manipulated by either taking away the MLL gene or inhibiting the enzyme to see if their growth can be affected.

There are even broader implications, Korsmeyer says. Studies show the protein made by the MLL gene regulates some of the HOX genes, master genes that guide the formation of body tissues and organs. Malfunction of HOX genes has been implicated in several types of cancer that occur in tissues other than the blood system.

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