Journal
NATURE MEDICINE
Volume 18, Issue 2, Pages 298-303Publisher
NATURE RESEARCH
DOI: 10.1038/nm.2651
Keywords
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Funding
- US National Institutes of Health National Cancer Institute [P30 CA016087-30, 5 P30CA16087-31]
- Damon Runyon Cancer Research Foundation
- US National Institutes of Health [RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655, RO1GM088847, R01CA120196, R01CA155743]
- The Leukemia & Lymphoma Society
- The V Foundation
- American Cancer Society [RSG0806801]
- Dana Foundation
- Feinberg Lymphoma Pilot grant
- Fund for Scientific Research of Flanders
- US National Library of Medicine [1R01LM010140-01]
- Eastern Cooperative Oncology Group tumor bank
- Northeast Biodefense Center [U54-AI057158]
- Stand Up To Cancer Innovative Research Award
- Chemotherapy Foundation
- Rally Across America Foundation
- Swim Across America Foundation
- Spanish Ministerio de Ciencia e Innovacion [BFU2009-09074, MEC-CONSOLIDER CSD2007-00023]
- Generalitat Valenciana [PROMETEO2006/134]
- EU [UE-HEALH-F2-2008-201666]
- Institut du Cancer
- Association Laurette Fugain
- Ligue National Contre le Cancer
- INSERM
- CEA
- StemPole
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T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling(1). 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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