Credit: Thomas Semkow
Blocking the action of an enzyme “switch” needed to activate tumor growth may be a practical strategy for treating T-cell acute lymphoblastic leukemia (T-ALL), new research suggests.
The study showed that this enzyme, JMJD3, acts as a cancer “on” switch by splitting off a chemical methyl group of another protein that is usually methylated by the tumor-suppressing enzyme PRC2.
PRC2 acts, in turn, as an “off” switch for cancer cell proliferation.
The researchers previously showed that this destabilizing and cutting loose of PRC2 leads to activation of the NOTCH1 pathway, a process common to many cancers but especially active in at least half of all people with T-ALL.
The team said the drug manufacturer GlaxoSmithKline is already developing an investigational compound called GSKJ4, whose treatment path follows the biological road map revealed in this research.
“Our investigations are showing incredible promise in fighting this disease at the transcriptional level,” said Iannis Aifantis, PhD, of NYU Langone Medical Center in New York.
“We are blocking the action of enzymes controlling the transcription of proteins involved in leukemia, rather than attempting to directly suppress cancer genes.”
Dr Aifantis and his colleagues described this approach in a letter to Nature.
The group’s findings are the culmination of several years of research to unravel precisely how PRC2 suppresses tumor growth since the team first reported the phenomenon in leukemia.
For the current study, the researchers investigated precisely how demethylation triggers the chain of events that evicts PRC2 from cells, thereby removing PRC2 suppression of NOTCH1, which directly binds to and activates cancer-causing genes.
Specifically, they focused on a protein controlled and methylated by PRC2 called H3K27, as well as two other enzymes closely tied to H3K27—JMJD3 and UTX.
The study showed that JMJD3 was highly active in both mice and human leukemia cells at all stages of tumor growth and development. By contrast, UTX was not overexpressed in leukemia, but it was highly active in noncancerous mouse and human cells.
When mice and human leukemia cells were treated with the experimental drug GSKJ4, JMJD3 activity stopped, and all cancer cells eventually died.
Subsequent experiments showed that, in leukemic JMJD3 knockout mice, NOTCH1 activity declined, while UTX activity remained the same.
The disease also progressed much faster in mice bred without UTX, while mice lived longer if they produced UTX. These findings suggest that UTX production controls several tumor-suppressing genes.
To further confirm their findings, the researchers screened more than 200 blood samples from children and adults with T-ALL, revealing several common mutations in UTX.
Dr Aifantis said plans are underway to test GSKJ4 against human leukemia cells transplanted in mice. Other experiments will use the drug in combination with standard chemotherapy in animals with leukemia.
“Our report serves as a valuable reminder of just how complex cancers like T-cell acute lymphoblastic leukemia can be,” Dr Aifantis said, “and that enzymes can play many, even opposing, roles in both tumor growth and suppression.”
