Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a malignancy characterized by the uncontrolled proliferation of immature myeloid cells, often due to a block in differentiation. Recent therapeutic strategies aimed at promoting the differentiation of these immature cells have shown promise in AML, although such treatments are typically limited to patients with specific mutations. In this study, we explore the potential of targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) as a means to induce differentiation of AML blast cells into a more mature myeloid phenotype and improve survival outcomes in murine models of AML.

Methods: The EZH2 inhibitor EPZ011989 (EPZ) was evaluated in AML cell lines, primary AML samples, and normal CD34+ stem cells. We assessed pharmacodynamic changes in H3K27me3, examined differentiation, cell growth, and colony formation, and conducted in vivo therapeutic studies, including the impact on primary AML cell engraftment.

Results: EPZ effectively inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition led to a significant reduction in colony formation in multiple AML cell lines and primary AML samples, while normal CD34+ stem cells showed no such effects. In AML cells, EPZ induced phenotypic markers of differentiation. Moreover, pretreatment of primary AML cells with EPZ significantly delayed engraftment and extended overall survival when these cells were engrafted into immunodeficient mice.

Conclusions: While EZH2 silencing has been linked to promoting AML pathogenesis in MDS/MPN, our findings suggest that therapeutic inhibition of EZH2 in established AML could improve survival outcomes. This highlights EZH2 inhibition as a potential strategy for enhancing differentiation and prolonging survival in AML patients.