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Researchers discover 'Achilles' heel' for lymphoid leukemia

An international research team coordinated at the IRCM in Montral found a possible alternative treatment for lymphoid leukemia. Led by Dr. Tarik Mry, the IRCM's President and Scientific Director, the team discovered a molecule that represents the disease's "Achilles' heel" and could be targeted to develop a new approach that would reduce the adverse effects of current treatments such as chemotherapy and radiation therapy. The study's results are being published today in the prestigious scientific journal Cancer Cell.

The researchers' results have direct implications for the treatment of acute lymphoblastic leukemia (ALL), one of the four most common types of leukemia. ALL is a cancer of the bone marrow and blood that progresses rapidly without treatment. Current treatments consist of chemotherapy and radiation therapy, which are both highly toxic and non-specific, meaning that they damage healthy cells as well as tumour tissues.

"Even when effective, patients can suffer dramatic side effects from these treatments," says Dr. Mry, who is also Director of the Hematopoiesis and Cancer research unit at the IRCM and corresponding author of the study. "Therefore, they would directly benefit from an improved therapy that could reduce the necessary dose of radiation or chemotherapy, and thus their side effects, while maintaining the treatments' efficacy. Therapies that target specific molecules have shown great promise. This is why, for the past 20 years, I have been studying a molecule called Gfi1, which plays an important role in the development of blood cells and cancer."

When normal cells are transformed into tumour cells, the body responds by activating a tumour suppressor protein that induces cell death. Tumour cells must therefore counteract cell death in order to survive.

"With this study, we found that leukemic cells depend on the Gfi1 molecule for their survival," explains Dr. Cyrus Khandanpour, co-first author of the study and University Hospital physician at University Duisburg-Essen in Germany. "In fact, this molecule helps the malignant cells avoid death by hindering the activity of the tumour suppressor protein. Our results show that when Gfi1 is removed in mice that suffer from T-cell leukemia, the tumour disappears and the animals survive."

"Following this discovery, we wanted to test whether it could be used as a viable approach to treat leukemia in humans," adds Dr. Mry. "We transplanted cells from a patient with T-cell leukemia into a mouse. We then inhibited the Gfi1 molecule using a commercially-available agent, and noticed that it stopped the expansion of human leukemia in the bone marrow, peripheral blood and spleen, without leading to adverse effects."

"These results are a significant indication that therapies targeting the molecule Gfi1 would work in human patients," says Dr. H. Leighton Grimes, co-corresponding author of the study from the Cincinnati Children's Hospital Medical Center. "In fact, if our results translate to patients, they could improve the prognosis of people suffering from lymphoid malignancies," adds Dr. James Phelan, the study's co-first author and recent PhD graduate in Dr. Grimes' laboratory.

"Our study suggests that a molecular-based therapy targeting Gfi1 would not only significantly improve response rates, but may also lower effective doses of chemotherapy agents or radiation, thereby reducing harmful side effects," concludes Dr. Khandanpour, who is also a visiting scientist at the IRCM. "Gfi1 represents an Achilles' heel for lymphoid leukemia and we are continuing to work so that our approach may soon move to clinical trials."


Contact: Julie Langelier
Institut de recherches cliniques de Montreal

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