Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations

Alqazzaz, Mona A.; Luciani, Genna M.; Vu, Victoria; Machado, Raquel A.C.; Szewczyk, Magdalena M.; Adamson, Ella C.; Cheon, Sehyun; Li, Fengling; Arrowsmith, Cheryl H.; Minden, Mark D.; Barsyte-Lovejoy, Dalia

doi:10.1016/j.exphem.2023.11.009

Cited by 1 publication

(1 citation statement)

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“…This is even the case in patients with established EZH2-inactivating mutations. While none of the samples in our current series included EZH2 mutations, these patients might also benefit from EZH2 inhibition based on a recent study that describes that cell death pathways are upregulated in AML patient cells with mutant EZH2 [30].…”

Section: Discussionmentioning

confidence: 99%

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

Fobare,

Elgamal,

Wunderlich

et al. 2024

Cancers

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Background: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models. Methods: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted. Results: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice. Conclusions: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.

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Section: Discussionmentioning

confidence: 99%