Experimental Drug Blocks Leukemia Growth in Mouse Model System
By LabMedica International staff writers
Posted on 14 Mar 2016
An experimental drug that blocks the activity of a specific histone demethylase enzyme was found to cure the TAL-1 form of acute T-cell lymphoblastic leukemia (T-ALL) in a mouse model system.Posted on 14 Mar 2016
T-ALL afflicts mostly children, with more than 500 new pediatric diagnoses in the United States annually. The leukemia, which occurs in a child's developing T-cells, is fatal in about 1 in 4 cases. In the remaining patients with the disease, T-ALL requires intense levels of chemotherapy or radiation.
Image: Mouse spleens that were infiltrated by TAL-1-positive T-ALL leukemia cells taken from human patients, with leukemia cells shown in brown. Images on the right are from mice treated with GSK-J4, while the mice on the left were not treated with the compound (Photo courtesy of Dr. Aissa Benyoucef, Ottawa Hospital Research Institute).
Investigators at the Ottawa Hospital Research Institute (Canada; www.ohri.ca) concentrated their efforts on a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL-1.
They reported in the March 1, 2016, issue of the journal Genes & Development that this subtype of T-ALL was uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase enzyme UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome).
The investigators used a model system in which human T-ALL cells were transplanted into mice. Some of the animals were treated with the experimental drug GSK-J4, which is a potent cell-permeable inhibitor of the histone H3 lysine 27 (H3K27) demethylase JMJD3, an essential component of regulatory transcriptional chromatin complexes. They found that this drug blocked UTX activity and stopped the growth of TAL-1 type cancer cells. After three weeks of treatment the number of cancer cells in the bone marrow decreased by 80%, and the drug did not seem to harm normal cells or have any short-term effects on other organs of the body. The treatment was specific for the TAL-1 subtype, and did not prevent growth of any other types of T-ALL.
"It is very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease," said senior author Dr. Marjorie Brand, a senior scientist at the Ottawa Hospital Research Institute. "Unlike current therapies, ours targets the offending gene without harming the rest of the body. Learning how a disease works at a molecular level needs to happen before any kind of successful drug can be developed. You need to do laboratory studies to find the right treatment and prove it works."
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Ottawa Hospital Research Institute