Genes can play “good cop, bad cop” or Dr. Jekyll and Mr. Hyde. Just ask Taka Maeda, M.D., Ph.D., a new assistant professor in City of Hope’s Department of Hematopoietic Stem Cell & Leukemia Research.
Maeda has studied a mouse gene called LRF — short for leukemia/lymphoma-related factor — for more than five years, trying to understand how it regulates the immune system.
Together with former colleagues at Memorial Sloan-Kettering Cancer Center in New York, Maeda looked at that gene in certain stem cells that can form the many different types of cells in the blood. (Stem cells are all-purpose cells that can develop into a variety of different specialized cells).
The stem cells Maeda studies are important to the immune system because they can become both B-cells and T-cells, which are potent defenders against disease and foreign invaders.
The investigators wanted to know exactly what the LRF gene does, so they launched a plan. They would look at what happens when mice do not have that gene at all.
Maeda and his former colleagues used a sort of genetic trick to eliminate the LRF gene from mouse DNA. What they found was surprising. First, the mice made no B-cells at all. And second, their bodies made T-cells in the wrong place.
The group recently reported their work in the journal Science.
These findings show that when LRF is in its “good cop” phase and is doing what it is supposed to do, the gene plays a big part in something crucial to the immune system: the process of creating B-cells and T-cells.
However, other experiments have hinted that the gene has a dark side, too.
When the researchers took the gene away from the mouse DNA, cells were almost resistant to cancer. That means that even though the gene is necessary for proper development of the immune system, something about its presence actually leaves a cell vulnerable to cancer.
And experiments confirm that. When the researchers increased LRF levels in their model, they saw aggressive leukemia and lymphoma, Maeda said.
Those findings echo what he has seen in human patients. He has observed high levels of LRF in tissues of patients with a form of B-cell lymphoma.
Before coming to the United States to study cancer in mice, Maeda received his advanced degrees at Nagoya University in Japan. Now at City of Hope he says he hopes to “get back to humans.”
Drugs that target the “bad cop” or “Mr. Hyde” side of the LRF gene might become therapies for lymphoma or leukemia, possibilities that Maeda plans to pursue at City of Hope. He also is analyzing a different gene associated with cancer, this one for a more personal reason.
“In Japan, I had a leukemia patient with a mutation in that gene,” he said. “He was 25 years old when he died, and I was his primary doctor. I feel like it is fate to work on something related to this patient.”
The lowdown on leukemia and lymphoma
Leukemia and lymphoma are blood cancers.
Physicians recognize four kinds of leukemia, which may be either acute (rapidly progressing) or chronic (involving a slower progression). Lymphoma, meanwhile, grows from the lymphatic system and is composed of two major types: Hodgkin’s and non-Hodgkin’s.
For more information about these cancers and their diagnosis and treatment, visit the Leukemia & Lymphoma Society on the Web, or read more about them on City of Hope’s cancer information site.
