Chromatin-Based Classification of Genetically Heterogeneous AMLs into Two Distinct Subtypes with Diverse Stemness Phenotypes

Yi, Guoqiang; Wierenga, Albertus T. J.; Petraglia, F.; Narang, Pankaj; Janssen-Megens, Eva M.; Mandoli, Amit; Merkel, Angelika; Berentsen, Kim; Kim, Bowon; Matarese, Filomena; Singh, Abhishek A.; Habibi, Ehsan; Prange, K.H.M.; Mulder, André B.; Jansen, Joop H.; Clarke, Laura; Heath, Simon; Reijden, Bert A. van der; Flicek, Paul; Yaspo, Marie–Laure; Gut, Marta; Bock, Christoph; Schuringa, Jan Jacob; Altucci, Lucia; Vellenga, Edo; Stunnenberg, Hendrik G.; Martens, Joost H.A.

doi:10.1016/j.celrep.2018.12.098

Cited by 39 publications

(64 citation statements)

References 62 publications

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“…In order to assess whether cellular transformation in AML unmasked intrinsic regulatory activity of TEs, we identified putative regulatory TEs by focusing on repeat families that were frequently associated with open chromatin in AML. To this end, we analysed DNase-seq data from 32 AML samples generated by the Blueprint epigenome project (Yi et al, 2019), and compared them with data from differentiated myeloid cells (macrophages, monocytes) from the same consortium ( Figure 1A).…”

Section: Identification Of Putative Aml-specific Regulatory Tesmentioning

confidence: 99%

“…A-DAR elements overlapping DHSs in at least one sample were selected, and a correlation matrix built based on the patterns of DHS overlap between samples. These were compared with the AML mutational profiles extracted from the respective publications (Assi et al, 2018;Yi et al, 2019). Correlation coefficients between AML samples sharing a particular mutation were compared with correlation coefficients between samples without the mutation.…”

Section: Mutational Profile Analysismentioning

confidence: 99%

“…Notably, over 70% AML patients have a genetic abnormality in one epigenetic modifier (Papaemmanuil et al, 2016). Interestingly, altered chromatin landscape, including DNA methylation (Figueroa et al, 2010), histone modifications and chromatin accessibility (Assi et al, 2018;Yi et al, 2019) establishes different AML subtypes linked to specific genetic alterations.…”

Section: Introductionmentioning

confidence: 99%

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Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Deniz

Ahmed

Todd

et al. 2019

Preprint

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Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated healthy myeloid cells. A subset of these AML-associated ERVs harbour enhancerspecific histone modifications, and are bound by hematopoiesis-associated transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic editing and simultaneous epigenetic silencing of multiple ERV copies, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV, through modulating expression of APOC1 gene, leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes. 10% or more of the AML samples ( Figure 1B). Five of these families were highly enriched across all samples, including macrophages and monocytes, as well as mobilized CD34+ cells (data from the Roadmap epigenomics project), suggesting little cell specificity. The remaining seven families displayed more variability between AML samples and, notably, tended to display little to no enrichment in differentiated myeloid cells ( Figure 1B). Nearly all families were also DHS-enriched in CD34+ cells, suggesting an association with a stem cell state. The exception was the LTR2B family, whose DHS enrichment appeared to be AML-specific. Analysis of an independent

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Section: Identification Of Putative Aml-specific Regulatory Tesmentioning

confidence: 99%

Section: Mutational Profile Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Deniz

Ahmed

Todd

et al. 2019

Preprint

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“…Our study adds to a growing body of data demonstrating that enhancer biology is integral to the development of hematologic malignancies. While AML is very heterogeneous from a genomic standpoint, recent work demonstrates that there are only a few epigenetic disease subtypes 20,26 . Thus, understanding the epigenetic dysfunction in AML may provide broad insight into therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

“…We identified 42,124 active enhancers (defined as high H3K4me1, low H3K4me3 and high H3K27ac) across all 4 conditions (Table S4). To validate these findings in human AML, we mapped our enhancers to orthologous human genomic coordinates and assessed overlap of enhancers only active in the CSF3R T618I /CEBPA V314VW condition with those present in human AML with mutant CEBPA 20 . We observed a significant enrichment of overlap between our mouse AML enhancers with those found in human AML, suggesting conserved biology ( Figure S5D).…”

Section: Cebpa Mutations Disrupt Activation Of Myeloid Lineage Enhancersmentioning

confidence: 98%

Myeloid Lineage Enhancers Drive Oncogene Synergy in CEBPA/CSF3R Mutant Acute Myeloid Leukemia

Braun

Okhovat

Coblentz

et al. 2019

Preprint

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Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity. B.J.D.

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Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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Acute myeloid leukemia (AML) is a complex disease characterized by a diverse range of recurrent molecular aberrations that occur in many different combinations. Components of transcriptional networks are a common target of these aberrations, leading to network‐wide changes and deployment of novel or developmentally inappropriate transcriptional programs. Genome‐wide techniques are beginning to reveal the full complexity of normal hematopoietic stem cell transcriptional networks and the extent to which they are deregulated in AML, and new understandings of the mechanisms by which AML cells maintain self‐renewal and block differentiation are starting to emerge. The hope is that increased understanding of the network architecture in AML will lead to identification of key oncogenic dependencies that are downstream of multiple network aberrations, and that this knowledge will be translated into new therapies that target these dependencies. Here, we review the current state of knowledge of network perturbation in AML with a focus on major mechanisms of transcription factor dysregulation, including mutation, translocation, and transcriptional dysregulation, and discuss how these perturbations propagate across transcriptional networks. We will also review emerging mechanisms of network disruption, and briefly discuss how increased knowledge of network disruption is already being used to develop new therapies.

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Chromatin-Based Classification of Genetically Heterogeneous AMLs into Two Distinct Subtypes with Diverse Stemness Phenotypes

Cited by 39 publications

References 62 publications

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Myeloid Lineage Enhancers Drive Oncogene Synergy in CEBPA/CSF3R Mutant Acute Myeloid Leukemia

Transcriptional networks in acute myeloid leukemia

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