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Abstract:Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synerg… Show more
“…Interestingly, spreading targets that overlapped with either broad H3K4me3 or super-enhancers were significantly more sensitive to DOT1L inhibition than spreading MLL-AF4 targets alone (Figure S7D). This indicates that there are further subdivisions of activity within spreading targets themselves, something that may explain recent results looking at DOT1L and BRD4 cooperation (Gilan et al., 2016). …”
SummaryUnderstanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.
“…Interestingly, spreading targets that overlapped with either broad H3K4me3 or super-enhancers were significantly more sensitive to DOT1L inhibition than spreading MLL-AF4 targets alone (Figure S7D). This indicates that there are further subdivisions of activity within spreading targets themselves, something that may explain recent results looking at DOT1L and BRD4 cooperation (Gilan et al., 2016). …”
SummaryUnderstanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.
“…While it is not uncommon for variations in stock solution to cause differing compound potency and toxicity (Kannt and Wieland, 2016), a reduced dose could have an impact on I-BET151 efficacy. Indeed, recent work from authors of the original study reported I-BET151 administered at 10 mg/kg had no impact on survival in a MLL-AF9 leukaemia mouse model (Gilan et al, 2016), while I-BET151 administered at 15 mg/kg did provide a survival benefit in a mouse model of NPM1c AML, albeit with a smaller effect size (Dawson et al, 2014). 10.7554/eLife.25306.006Figure 3.Maximal tolerated dose in an I-BET151 treated xenograft mouse model of MLL-fusion leukaemia.Female NOD-SCID mice were conditioned with Busulfan and intravenously injected with 1 × 10 7 MV4;11 cells in vehicle (PBS).…”
Section: Resultsmentioning
confidence: 99%
“…Additionally, evidence indicating potential acquired resistance to BET inhibitors has been reported (Fong et al, 2015; Kumar et al, 2015; Rathert et al, 2015), along with studies which have found that treatment with combinatorial drugs can mitigate acquired resistance (Asangani et al, 2016; Kurimchak et al, 2016; Yao et al, 2015). Furthermore, a recent study reported synergistic effects of combinatorial treatment with a disruptor of telomeric silencing 1-like (DOT1L) inhibitor and I-BET151 in MLL cells and mouse leukaemia models (Gilan et al, 2016). Studies have also addressed the nonclinical safety of BET inhibition and found that BET bromodomain inhibition can impact normal intestinal homeostasis and repair (Nakagawa et al, 2016).…”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al., 2011). Further, I-BET151 resulted in a statistically significant decrease in BCL2 expression in MV4;11 cells, but not in K-562 cells; again this is similar to the findings reported in the original study (Figure 3D; Dawson et al., 2011). We did not find a statistically significant difference in survival when testing I-BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported increased survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Differences between the original study and this replication attempt, such as different conditioning regimens and I-BET151 doses, are factors that might have influenced the outcome. We also found I-BET151 treatment resulted in a lower median disease burden compared to vehicle control in all tissues analyzed, similar to the example reported in the original study (Supplementary Figure 16A; Dawson et al., 2011). Finally, we report meta-analyses for each result.DOI:
http://dx.doi.org/10.7554/eLife.25306.001
“…The same difficulties in establishing causal links apply also in this setting. In that respect exploring metabolic dependencies in settings where a genetic lesion modifies chromatin as in MLL-rearranged leukemias 125, 126 , or pediatric brain tumors and sarcomas with histone mutations 127, 128 , might prove fruitful as these cases could be particularly susceptible to a disruption in metabolism.…”
The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.
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