Agents that inhibit the protein kinase JAK3 could prove effective for treating natural killer/T-cell lymphoma (NKTL), according to research published in Blood.
Researchers investigated the role the cancer-promoting gene EZH2 plays in NKTL.
This revealed that EZH2 activity is regulated by JAK3, and a JAK3 inhibitor could significantly reduce the growth of NKTL cells.
Specifically, the team discovered that JAK3 activation leads to phosphorylation of EZH2.
This prompts the dissociation of EZH2 from the PRC2 complex and leads to decreased global H3K27me3 levels.
EZH2 then shifts from its normal function of suppressing gene expression to activating genes—specifically, upregulating a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness.
And this leads to the development of NKTL.
“As JAK3 is often mutated and activated in natural killer/T-cell lymphoma cells, this finding is particular intriguing, as it suggests a predominant non-catalytic function of EZH2 in JAK3-mutant natural killer/T-cell lymphoma,” said study author Wee-Joo Chng, MB ChB, PhD, of the National University of Singapore.
“Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer.”
The researchers also found that a JAK3 inhibitor could significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner.
However, compounds that have recently been developed to inhibit EZH2 methyltransferase activity did not have the same effect.
“Moving forward, a biomarker strategy might be needed to ensure appropriate application of EZH2 inhibitors,” Dr Chng said.
“This will help to identify tumors where EZH2 requires its catalytic activity or is actually acting through non-catalytic function. At the same time, we need to develop therapies that can target the non-catalytic function of EZH2.”
