Contrasting stage-dependent requirements during AML evolution identify EZH2 as a therapeutic target in AML
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ABSTRACT:
PROVIDER: PRJNA448835 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6945510_1.fastq.gz | Fastqsanger.gz | |||
| SRR6945510_2.fastq.gz | Fastqsanger.gz | |||
| SRR6945520.fastq.gz | Fastqsanger.gz | |||
| SRR6945530.fastq.gz | Fastqsanger.gz | |||
| SRR6945501_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of the lysine histone methyltransferase EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. We study this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukemia (AML). Remarkably, we observe diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by different AML-associated fusion-oncogenes. During disease maintenance we demonstrate that Ezh2 functions as an oncogene that may be therapeutically targeted. In contrast, Ezh2 acts as a tumour suppressor during AML induction and loss-of-function EZH2 mutations occur early in AML patient samples and confer a poor prognosis. Integrated genomic analysis demonstrates that different expression programmes are de-repressed during AML induction and maintenance following Ezh2 loss. During disease induction, Ezh2 loss de-represses a subset of bivalent promoters that resolve towards gene activation, inducing a feto-oncogene programme including genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, we further identify EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.
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Project description:Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that loss of Ezh2 derepresses different expression programs during disease induction and maintenance. During disease induction, Ezh2 loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a feto-oncogenic program that includes genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2 and its potential therapeutic implications.
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Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.
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Project description:The Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is an essential epigenetic modifier able to methylate lysine 27 on histone H3 (H3K27) to induce chromatin compaction, protein complex recruitment and ultimately transcriptional repression. Hematologic malignancies, including Diffuse Large B cell lymphoma (DLBCL) and Acute myeloid leukemia (AML) have shown a high EZH2-mutation frequency (>20%) associated with poor clinical outcomes. Particularly, two distinct oncogenic mutations, so-called gain-of-function (Y641F and A677G) and loss-of-function (H689A and F667I) are found in the catalytic domain of EZH2. In this study, a comprehensive multi-omics approach was employed to characterize downstream effects of H3K27me3 deposition driven by EZH2 mutations. Human embryonic kidney cells (HEK293T) were transfected to generate three stable EZH2 mutants: EZH2(Y641F), EZH2(A677G), and EZH2(H689A/F667I), which were validated via immunoblotting and DIA-MS-based histone profiling assay. The histone profiling assay demonstrated a significant increase of approximately two-fold in H3.1/H3.3K27me3 for Y641F EZH2 mutant. There was a modest increase in the combinatorial PTMs H3.1/H3.3K27me3K36me1 and a significant depletion in H3.1 and H3.3 K27me2. The most depleted peptide was H3.3K27me2K36me2. For the A677G EZH2 mutant, the assay demonstrated an enrichment on H3.1/H3.3K27me3, combinatorial K27me3K36me1 and a slight increase in K27me1 and K18ac but only on H3.1. The most depleted peptide was H3.3K27me2K36me2. The H689A/F667I cell line has the most alterations in global histone PTMs. The most highly enriched were H3.1/H3.3K36me2, H3.1K9me3 and H3.3K36me1. The most depleted modifications were H3.1K23ac and H3.1K27me3.
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