Pluto Bioinformatics

GSE112724: Contrasting stage-dependent requirements during AML evolution identify EZH2 as a therapeutic target in AML

Bulk RNA sequencing

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. SOURCE: Brian Huntly (bjph2@cam.ac.uk) - Wellcome Trust–MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge