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| Item Type: | Article |
|---|---|
| Title: | Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML |
| Creators Name: | Basheer, F., Giotopoulos, G., Meduri, E., Yun, H., Mazan, M., Sasca, D., Gallipoli, P., Marando, L., Gozdecka, M., Asby, R., Sheppard, O., Dudek, M., Bullinger, L., Döhner, H., Dillon, R., Freeman, S., Ottmann, O., Burnett, A., Russell, N., Papaemmanuil, E., Hills, R., Campbell, P., Vassiliou, G.S.. and Huntly, B.J.P. |
| Abstract: | Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that loss of derepresses different expression programs during disease induction and maintenance. During disease induction, loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a feto-oncogenic program that includes genes such as , whose overexpression phenocopies loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2 and its potential therapeutic implications. |
| Keywords: | Acute Myeloid Leukemia, Animal Disease Models, Bone Marrow Cells, Bone Marrow Transplantation, Cohort Studies, Disease Progression, Enhancer of Zeste Homolog 2 Protein, Gene Frequency, Genetic Transduction, Histones, Homologous Transplantation, Inbred C57BL Mice, Loss of Function Mutation, Prognosis, Survival Rate, Tumor Cell Line, Animals, Mice |
| Source: | Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Volume: | 216 |
| Number: | 4 |
| Page Range: | 966-981 |
| Date: | 1 April 2019 |
| Official Publication: | https://doi.org/10.1084/jem.20181276 |
| PubMed: | View item in PubMed |
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