June 13, 1997

Gene linked to acute leukemia under investigator’s microscope

Gene linked to acute leukemia under investigator's microscope

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Dr. Scott Hiebert, here working with Dr. Jennifer Westendorf, is studying a gene that may play a role in a large percentage of acute leukemia cases.

Vanderbilt University Medical Center researchers are currently investigating a gene that may play a role in 35 percent of all acute myeloid leukemia (AML) cases as well as 25 percent of all childhood acute lymphocyctic leukemia (ALL) cases.

Through a process called chromosomal translocation, acute leukemia is caused, on the molecular level, when pieces of two chromosomes break off and trade places.

The gene VUMC investigators are studying, AML-1, is heavily involved in this chromosome-swapping process, which leads to the proliferation of leukemia cells in the bone marrow.

"Because these chromosomal translocations are present in this particular type of leukemia, they are likely the primary event that leads to leukemia," said Dr. Scott Hiebert, associate professor of Biochemistry.

The gene Hiebert is investigating, AML-1, is a transcription factor that is disrupted by the (8;21) translocation in AML and the (12;21) translocation in ALL.

"AML-1 is one of the first transcription factors that is involved in translocations in both AML and ALL," said Hiebert.

In both cases, AML-1 is interrupted and another gene replaces part of it. This leads to a disruption of the normal expression of genes regulated by AML-1, which eventually causes the leukemia, Hiebert said.

When Hiebert began to analyze AML-1 function, he discovered that it activated a large number of genes in myeloid and lymphoid cells, whereas the translocated forms of AML-1 inactivated these same genes.

"The big goal now is to discover how these translocation proteins interfere with AML-1 function," Hiebert said. "We know that AML-1 is needed for myeloid cell differentiation and that the translocation proteins block this process. Now we are trying to understand how this occurs.

"Normally cells that do not differentiate die. Leukemia cells do not necessarily grow rapidly but they do grow and don't die," said Hiebert.

An understanding of how AML-1 works in the cell could lead to many advancements in the treatment or prevention of acute myeloid leukemia and B-cell leukemia, Hiebert said.