Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers

Glass, Jacob L.; Hassane, Duane C.; Wouters, Bas J.; Kunimoto, Hiroyoshi; Avellino, Roberto; Garrett-Bakelman, Francine E.; Guryanova, Olga A.; Bowman, Robert L.; Redlich, Shira; Intlekofer, Andrew M.; Meydan, Cem; Qin, Tingting; Fall, Mame P.; Alonso, Alicia; Guzmán, Mónica L.; Valk, Peter J.M.; Thompson, Craig B.; Levine, Ross L.; Elemento, Olivier; Delwel, Ruud; Melnick, Ari; Figueroa, María E.

doi:10.1158/2159-8290.cd-16-1032

Cited by 112 publications

(160 citation statements)

References 47 publications

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“…However, despite the wide variety of molecular aberrations observed, clustering of large AML cohorts based on global transcriptomic or epigenomic data generally reveals only a small number of clusters. 19,66,238,240,255 This may reflect the fact that although the large transcriptional networks in eukaryotic cells have many theoretical states, only a small number of these are stable and accessible. What is also becoming clearer is that leukemic transcriptional networks are highly plastic, and emerging data suggest that in addition to being implicated in leukemogenesis alterations to transcriptional networks may play a role in AML progression, resistance, and relapse.…”

Section: Discussionmentioning

confidence: 99%

“…In a mouse model, loss of TET2 can cooperate with Flt3 ‐ITD mutations to remodel DNA methylation, including at the Gata 2 locus with concomitant reduction in Gata 2 mRNA expression, and increased methylation at the GATA2 locus is also observed in AML with mutated TET2 and FLT3 ‐ITD . Furthermore, a high‐resolution study of genome‐wide cytosine methylation changes found AML‐specific changes in methylation associated with active HSC enhancers, but not at promoters . Clustering based on genome‐wide methylation patterns in primary AML samples reflected known molecular defects, suggesting that individual molecular aberrations, including mutations in IDH and DNMT3A , lead to specific changes in DNA methylation .…”

Section: Global Alterations In Chromatin Organizationmentioning

confidence: 95%

“…237 Furthermore, a high-resolution study of genome-wide cytosine methylation changes found AML-specific changes in methylation associated with active HSC enhancers, but not at promoters. 238 Clustering based on genome-wide methylation patterns in primary AML samples reflected known molecular defects, suggesting that individual molecular aberrations, including mutations in IDH and DNMT3A, lead to specific changes in DNA methylation. 238 However, an integrated analysis of genetic and epigenetic variation during AML progression concluded that epigenetic diversification during AML progression may be independent of the genetic landscape.…”

Section: Dysregulation Mediated By Altered Cytosine Methylationmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Global Alterations In Chromatin Organizationmentioning

confidence: 95%

Section: Dysregulation Mediated By Altered Cytosine Methylationmentioning

confidence: 99%

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Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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“…Next we aimed to compare global DNA methylation patterns from AML patients carrying the R882H mutation with AML patients not containing it. Glass et al (2017) reported enhanced reduced representation bisulfite sequencing (ERRBS) DNA methylation profiles of 119 AML samples, 27 of them with R882H mutation (Glass et al, 2017). The data include CpGs covered between 10-400x, methylation changes were called requiring at least 3 samples to support the difference.…”

Section: Correlation Of Aml Patient Dna Methylation Profiles With Thementioning

confidence: 99%

Mutations of R882 in DNMT3A change flanking sequence preferences and cellular methylation patterns in AML

Emperle

Adam

Kunert

et al. 2019

Preprint

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DNMT3A R882 mutations are frequently observed in AML including the abundant R882H and the rare R882C, R882P and R882S. Using deep enzymology we show here that the DNMT3A-R882H has more than 70-fold altered flanking sequence preferences when compared with wildtype DNMT3A. The R882H flanking sequence preferences mainly differ on the 3' side of the CpG site, where they resemble DNMT3B, while 5' flanking sequence preferences of R882H resemble wildtype DNMT3A, indicating that R882H behaves like a DNMT3A/DNMT3B chimera. Activities and flanking sequence preferences of R882C, R882P and R882S were determined as well. Genomic methylation patterns after expression of wildtype DNMT3A and R882H in human cells reflect the flanking sequence preferences. R882H specific hypermethylation in AML patients are correlated with R882H flanking sequence preferences. The hypermethylation events are accompanied by R882H specific misregulation of several genes with strong cancer connection in AML patients, which are potential downstream targets of R882H.

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“…Based on our current unprecedented progress in describing the genetic and epigenetic landscape of AML, we know that aberrant differentiation is frequently, at least in part, driven by epigenetic deregulation. 5,6 Examples include mutations in genes involved in DNA methylation and modification of histone marks. Mutations in IDH2 are observed in 10% to 12% of patients with AML, while another 10% of patients carry mutations in the related IDH1 gene.…”

mentioning

confidence: 99%