EZH2 May Be Required for CML Initiation, Could Represent Therapeutic Target

A laboratory study found that the protein EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is required for chronic myeloid leukemia (CML) initiating cells to survive. Inhibiting EZH2 could represent a way to improve outcomes in tyrosine kinase inhibitor (TKI)-resistant CML.

Though TKIs have revolutionized treatment of CML and dramatically improved outcomes, resistance to the agents remains an issue. “To address the limitations of TKIs in CML therapy, alternative pathways required for leukemia initiating cells have been sought,” wrote study authors led by Stuart H. Orkin, MD, of Dana-Farber Cancer Institute in Boston.

PRC2 components can be overexpressed or mutated in a number of malignancies, and there are several ongoing trials of EZH2 inhibitors in other cancers. In the new study, researchers analyzed whether EZH2 plays a role in CML, both in vitro and in mice. The results were published in Cancer Discovery.

Using human CML cells, the researchers found that EZH2 was overexpressed in leukemia initiating cells. An experiment that reduced protein levels by as much as 90% clearly inhibited the growth of CML cells. Further, BCR-ABL1 mutational status did not change the apparent dependence of the cells on EZH2.

Next, the investigators used a mouse model to confirm whether blocking EZH2 might inhibit CML formation. “Deletion of Ezh2…markedly delayed disease development, as revealed by reduced leukemic cells,” they wrote. The deletion of the gene prolonged survival, though the mice did eventually die from CML due to an incomplete excision of the Ezh2 gene.

A further experiment showed that inactivating Ezh2 in preexisting leukemia initiating cells also had a profound effect, again prolonging survival of the mice. “Taken together, these results indicate that CML leukemia initiating cells require Ezh2 for their maintenance and ability to initiate leukemia,” the authors wrote.

A second mouse model using CRISPR/Cas9 gene editing techniques confirmed the findings. Also, gene editing was used to inactivate Ezh2 in mice with preexisting CML, to determine if targeting this pathway could actually act as a treatment in patients with CML. They found that it “greatly extended survival.”

“We have genetically defined a dependence of CML leukemia initiating cells on EZH2, thereby establishing a potential target for improved therapy,” the authors concluded. “Given the current clinical development of EZH2 inhibitors, our findings provide an experimental rationale for incorporating these agents into therapy of CML directed at disease eradication.”