Novel Leukemia Treatment Discovered in Mice
July 10, 2009
A new therapy may be on the horizon for leukemia patients. Although researchers have long believed that targeting cancer stem cells is critical to effectively treating cancer, they have been unable to successfully target them without also killing normal stem cells. Although a few genes that are critical to the survival of cancer stem cells have been identified, most of them are also critical to normal stem cell survival. For leukemia, the tide may have finally turned — thanks to the efforts of a research team led by JAX Adjunct Professor Shaoguang Li, M.D., Ph.D., who now conducts research at the University of Massachusetts Medical School in Worcester, and collaborators at the Dana-Farber Cancer Institute. The team recently reported that disrupting the normal function of the gene arachidonate 5-lipoxygenase (Alox5) protects mice against BCR-ABL-induced chronic myeloid leukemia (CML) by altering the biological processes of leukemia stem cells (LSCs) but not those of normal hematopoietic stem cells (HSCs) (Chen et al. 2009).
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JAX Professor Shaoguang Li, Ph.D. |
To conduct their research, Professor Li and colleagues used three JAX® Mice strains: C57BL/6J (B6, 000664), B6.129S2-Alox5tm1Fun/J (004155) - an Alox5-deficient mouse on a B6 background, and B6.SJL-Ptprca Pepcb/BoyJ (002014) (also known as "pep boy"). The latter is commonly used in transplantation studies such as this one because it carries the differential B cell antigen CD45.1 (as opposed to the CD45.2 antigen carried by the B6 strain) to help to distinguish donor and recipient cells from each other.
Before this study, Alox5 was known for its role in processing essential fatty acids into leukotrienes, important agents in the inflammatory response. However, Professor Li and his colleagues had long suspected its association with leukemia. Their suspicions were confirmed when BCR-ABL-induced CML did not develop in Alox5-deficient mice but did develop in those mice if they were engineered to also express an Alox5 transgene. Professor Li's team substantiated Alox5's role in CML by treating leukemic B6 mice with Gleevec® (imatinib) a kinase inhibitor and currently the most effective human leukemia medication, and Zileuton®, an asthma medication that inhibits the Alox5 pathway. Although imatinib, which targets more differentiated cancer cells, effectively treated CML in leukemic mice, Zileuton® was more effective, and joint treatment with both drugs was even more effective in prolonging the lives of the leukemic mice.
By conducting a series of transplantation experiments, Professor Li's team determined that Alox5 deficiency blocks differentiation, alters the cell cycle, and induces apoptosis of long term LSCs (LT-LSCs). The Alox5 signaling pathway must be studied in more detail before we know why it does not have the same effects on normal HSCs. Indeed, a better understanding of the pathways that distinguish cancer stem cells from normal ones may lead to new and more focused therapeutic targets for a variety of cancers.
Professor Li's and his team's results demonstrate for the first time that targeting a specific gene can completely inhibit only cancer stem cells in vivo. A clinical trial to target ALOX5 in human leukemia patients is being planned and will be the first of its kind to test the efficacy of an anti-stem cell strategy as a cancer therapy (The Jackson Laboratory 2009).
References
Chen Y, Hu Y, Zhang H, Peng C, Li S. 2009. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Gen Jun 7, [Epub ahead of print].
The Jackson Laboratory. 2009. A lethal cancer knocked down by one-two drug punch. Jackson Laboratory press release, June 7.
