St. Jude Unlocks Mystery of Very Aggressive Leukemia
- Loss of Arf gene in acute lymphoblastic leukemia makes some forms of this cancer resistant to treatment with imatinib, but blocking JAK kinases can restore the sensitivity of cells to this drug
Investigators at St. Jude have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are very aggressive and resistant to a drug that is effective in treating a different type of leukemia.
The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of ALL. Inactivation of both Arf genes allowed the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec®). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.
The St. Jude team also found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to ALL, in which Arf loss frequently occurs and imatinib treatment is far less effective. “This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage. This advantage might contribute to imatinib resistance in some way,” said Charles Sherr, M.D., Ph.D., a Howard Hughes Medical Institute Investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology. Sherr is senior author of a report on this work that appears in the April 17 issue of the Proceedings of the National Academy of Sciences.
The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is a co-author of the paper.
Moreover, the study provided evidence that imatinib resistance in mouse models of ALL did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds that inhibited enzymes called JAK kinases restored the cells’ sensitivity to imatinib.
The findings of this study are important because they suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation, and they point to a strategy for overcoming this resistance, according to the researchers. “Although our efforts to block JAK enzymes were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs,” said Richard Williams, M.D., PhD, a research fellow in Sherr’s laboratory and the lead author of the paper.
This work was supported in part by the Howard Hughes Medical Institute, a National Institutes of Health Cancer Center Core Grant and ALSAC.
About: St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization.
Modern Ways to Fight Leukemia
It is a well know fact that we live in the age of technology. It seems that with the help of it scientist and doctors have come up with one of the most ingenuous ways of fighting the disease. A team of people lead by Mary Laughlin has shown the world that by using an umbilical cord transplant of blood, immediately after the patient has gone through quite severe doses of chemo therapy or radiation, about one third of the people showed a remarkable recovery. This would have never been possible in other cases, with other treatments.
This was an actual alternative to the bone marrow transplant. Because of cases of mismatches between patient and possible donors, doctors thought of the idea of using cord blood for transfer which is very rich in stem cells. The success was immediate. The thins is that this is the a great alternative for patients with leukemia because the blood that is used for the transplant does not have to be an exact match to be effective ( as in the cases of the bone marrow transplant).
The actual way that this blood is collected is actually very simple and risk free for everybody. The blood is retrieved from the fresh placenta of a mother that has just given birth to a child. This way the blood is saved after this being frozen and stored for safe keeping. The stem cells that can be found in the umbilical cord are actually immature blood cells that have yet to grow in either a red blood cell a white cell or a platelet. This stem cells can be used after a case of chemo or radiation therapy. They are inserted in to the bone marrow of the patient so that the normal functions of producing normal healthy blood cells can begin again at full potential.
The fact is that the treatment was used intensively on children, because of the fact that they are not yet matured and that production of certain cells in their bodies is much more easy to do then in grown ups. For them creating a whole new immune system was actually quite easy. In the cases of older people usage of the treatment was not yet done because certainty of a good result did not exist. But, still, after trying it on grown ups too results have been found to be very impressive. By only using a small quantity like 2 ounces of cord blood, the sick body can regenerate its immune system. The best thing about it was the fact that the blood didn’t necessarily have to be a perfect match with the one of the donor.
A lot of work is still being done in this field and results are beginning to be more and more interesting.
