The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.
A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.
Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.
The new study, published in Cell Reports, provides some insight.
Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.
Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.
“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.
“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”
The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.
The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.
“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.
He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.
“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.
He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.
