City of Hope’s Takahiro “Taka” Maeda, M.D., Ph.D., is so convinced that knowing how blood cells develop will lead to better cancer therapy that he took time out from his career as a hematologist in Japan to investigate the topic.
Maeda traveled to the United States for several years’ additional training in a molecular genetics laboratory — an effort that paid off.
As a postdoctoral fellow in the lab of Memorial Sloan-Kettering Cancer Center geneticist Pier Paolo Pandolfi, M.D., Ph.D., Maeda spent five years trying to figure out what a gene initially named pokemon by Maeda’s colleagues does in B lymphocytes of the immune system.
Now, in the May 11 issue of Science, Maeda and his former colleagues report that they employed a molecular trick called a gene “knockout” to eliminate the pokemon gene — now known by the more sober name of LRF — from mouse DNA only in blood stem cells. They found that the knockout mice make no B-lymphocytes. But that is not all — they make T-cells in the wrong place: within the bone marrow, where normally only B-cells arise.
“We wanted to determine at what step in B-cell development LRF was operating,” explained Maeda. They found that LRF (which stands for leukemia/lymphoma-related factor) governs a crucial stage: the step when stem cells “decide” whether to become B- or T-cells.
The findings become even more significant when considered alongside results Maeda and colleagues published in Nature in 2005: When the researchers removed the LRF gene from the entire mouse genome, they found that cells cultured from mouse embryos were practically resistant to cancer.
Maeda and colleagues then engineered one more mouse — one that made too much LRF in immune cells. “When we made a mouse that expressed high LRF in B- and T-lymphocytes, we saw very aggressive leukemia and lymphoma in the mice,” he said. He also observed high LRF expression in human diffuse large B-cell lymphoma tissues taken from patients.
The story emerging from both the Science and Nature papers is that like many oncogenes, too much LRF can cause cancer, but some LRF is absolutely required for normal development — in this case, the healthy development of B-cells.
Prior to coming to the U.S., Maeda received his doctor of medicine and doctor of philosophy degrees at Nagoya University in Japan. The Pandolfi lab seemed like an ideal place for further training, he said, because the researchers used animal models to analyze cancer-causing “proto-oncogenes” and tumor suppressor genes, which protect against cancer.
“I went to Sloan-Kettering because I wanted to work on mouse models,” said Maeda, who as a clinician in Japan had done research using cultured cells. “I wanted to learn how these genes work in vivo. Now I think I am too much of mouse-model guy, so I need to get back to humans.”
Now, Maeda has arrived at City of Hope, ready to combine what he learned in the clinic in Japan with what he discovered studying mouse genes that cause leukemia and lymphoma. Maeda was appointed assistant professor in the Department of Hematopoietic Stem Cell & Leukemia Research earlier this year.
Maeda plans to continue to work on LRF, which represents a potential target for anti-cancer therapy. He also will analyze another unnamed 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.”
Maeda finds his new home a good place “to get back to humans.”
“At City of Hope, it is a great advantage to work with people doing clinical research and to have clinical samples available,” he said. Maeda will devote himself full-time to research in his lab, which is currently housed in the Flower Building.