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Contrasting stage-dependent requirements during AML evolution identify EZH2 as a therapeutic target in AML

ABSTRACT: Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of the lysine histone methyltransferase EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. We study this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukemia (AML). Remarkably, we observe diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by different AML-associated fusion-oncogenes. During disease maintenance we demonstrate that Ezh2 functions as an oncogene that may be therapeutically targeted. In contrast, Ezh2 acts as a tumour suppressor during AML induction and loss-of-function EZH2 mutations occur early in AML patient samples and confer a poor prognosis. Integrated genomic analysis demonstrates that different expression programmes are de-repressed during AML induction and maintenance following Ezh2 loss. During disease induction, Ezh2 loss de-represses a subset of bivalent promoters that resolve towards gene activation, inducing a feto-oncogene programme including genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, we further identify EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE112724 | GEO | 2019/03/07

REPOSITORIES: GEO

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Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.

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Contrasting stage-dependent requirements during AML evolution identify EZH2 as a therapeutic target in AML

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