Mutation Clonal Hierarchy in Acute Myeloid Leukemia.

Mutations in protein tyrosine phosphatase non-receptor type 11 ( ) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of mutations, we utilized single-cell DNA sequencing and identified that mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly mutations. The co-driver role of mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice.

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 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.