MLL-rearranged Leukemia is Dependent on Aberrant H3K79 Methylation by DOT1L
By K. Bernt, Nan Zhu, Amit U. Sinha, S. Vempati, Joerg Faber, Andrei Krivtsov, Zhaohui Feng, Natalie Punt, Amanda Daigle, L. Bullinger and 4 more. Cancer Cell, 2011
883 citations recorded by the source corpus.
Summary The 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 (LSC). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSC. Inactivation of Dot1l lead to down-regulation of direct MLL-AF9 targets and an MLL-translocation associated gene expression signature, while 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.
Subfields: Hematology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a8545633a26ee06499fbbb551d597760eaa89b85
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Hematology
In Molecular Biology
Citations in the corpus
- Cancer Genetics and Epigenetics: Two Sides of the Same Coin? (2012, background): “For example, the aberrant H3K79 methylation pattern mediated by DOT1L is required for the maintenance of the MLL translocation-associated oncogenic program (Bernt et al., 2011).”
- Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. (2013, methodology): “The MLL gene encodes a large multidomain protein (MLL) that regulates transcription of developmental genes including the HOX genes.1 The amino terminal portion of the protein contains regions that target MLL to DNA directly, whereas the carboxyl terminal portion of the protein contains a Su(Var)3-9,”
- Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor (2011, neutral): “The present paper and the paper by Bernt et al. (2011) (this issue of Cancer Cell) demonstrate clearly that ablation of DOT1L enzymatic activity, either by genetic knockdown of the entire protein or blockade of the catalytic active site, selectively kills cells bearing the MLL translocation in…”
- A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia (2016, background): “Although the precise molecular basis of these effects will need to be investigated in future studies, the transcriptional changes associated with KAT2A inhibition suggest that the effects may be secondary to inhibition of leukemogenic transcriptional programs, in a manner reminiscent of BRD4 and DOT”
- Epigenetic Determinants of Cancer. (2016, background): “…new possibilities in the area of epigenetic therapy—that is, where epigenetic changes are targeted for therapeutic reversal, as discussed further in Section 9 (Egger et al. 2004; Spannhoff et al. 2009; Kelly et al. 2010; Bernt et al. 2011; Daigle et al. 2011; Dawson et al. 2012; Azad et al. 2013).”
- Lessons from the cancer genome. (2013, neutral): “Interestingly, the DOT1L KMT, which methylates H3K79, is not itself mutated but becomes essential in MLL-translocated leukemias (Bernt et al., 2011).”