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MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
- Source :
- Cancer Cell. 20:66-78
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- SummaryThe histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
- Subjects :
- Cancer Research
Oncogene Proteins, Fusion
Cellular differentiation
Apoptosis
Biology
Methylation
Article
Histones
Mice
03 medical and health sciences
0302 clinical medicine
hemic and lymphatic diseases
medicine
Animals
Humans
Epigenetics
Myeloid Ecotropic Viral Integration Site 1 Protein
neoplasms
Myeloid Progenitor Cells
030304 developmental biology
Gene Rearrangement
Homeodomain Proteins
0303 health sciences
Lysine
Myelodysplastic syndromes
Cell Cycle
Cell Differentiation
Cell Biology
Histone-Lysine N-Methyltransferase
Methyltransferases
DOT1L
medicine.disease
Molecular biology
Hematopoiesis
Neoplasm Proteins
3. Good health
Leukemia
Cell Transformation, Neoplastic
Oncology
Genetic Loci
030220 oncology & carcinogenesis
Histone methyltransferase
Cancer research
H3K4me3
Protein Processing, Post-Translational
Myeloid-Lymphoid Leukemia Protein
Subjects
Details
- ISSN :
- 15356108
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Cancer Cell
- Accession number :
- edsair.doi.dedup.....02e37edfcaed6a1ace85f83760bd4cf4
- Full Text :
- https://doi.org/10.1016/j.ccr.2011.06.010