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The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
