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Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia
Open accessAbstract
T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling1. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2)2,3, in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3)4 by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.
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Metadata
- Authors
- Ntziachristos, P., Tsirigos, A., Vlierberghe, P. V., Nedjic, J., Trimarchi, T., Flaherty, M. S., Ferres-Marco, D., da Ros, V., Tang, Z., Siegle, J., Asp, P., Hadler, M., Rigo, I., Keersmaecker, K. D., Patel, J., Huynh, T., Utro, F., Poglio, S., Samon, J. B., Paietta, E., Racevskis, J., Rowe, J. M., Rabadan, R., Levine, R. L., Brown, S., Pflumio, F., Dominguez, M., Ferrando, A., & Aifantis, I.
- Venue
- Nature Medicine
- Published
- 2012-02
- Volume
- 18
- Issue
- 2
- Pages
- 298-302
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2038676786
- Cited by
- 526
- References
- 42
- FWCI
- 47.46
- Type
- journal article
- Language
- en
- Open access
- bronze
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