Histone methyltransferase <i>Suv39h1</i> deficiency prevents <i>Myc</i>‐induced chromosomal instability in murine myeloid leukemias

Vajen, Beate; Modlich, Ute; Schienke, Andrea; Wolf, Susanne; Skawran, Britta; Hofmann, Winfried; Büsche, Guntram; Kreipe, Hans; Baum, Christopher; Santos‐Barriopedro, Irene; Vaquero, Alejandro; Schlegelberger, Brigitte; Rudolph, Cornelia

doi:10.1002/gcc.22040

Cited by 9 publications

(6 citation statements)

References 30 publications

(38 reference statements)

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“…Loss of another HMT, SUV39H1, in MYC-driven myeloid leukemia prevented chromosomal instability in mouse models, indicating that it may be a potentially useful therapeutic target [175]. NV10, a small molecule inhibitor of SUV39H1, exhibited anti-cancer activity in vivo and in vitro in several cancers [176].…”

Section: Therapeutic Strategies: Targeting Epigenetic Mechanisms Imentioning

confidence: 99%

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

Poole

Riggelen

2017

Genes

137

114

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Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression.

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Section: Therapeutic Strategies: Targeting Epigenetic Mechanisms Imentioning

confidence: 99%

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

Poole

Riggelen

2017

Genes

137

114

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“…Study of a leukemia mouse model revealed histone methyltransferase Suv39h1-deficient hematopoietic cells that showed less critical short telomeres and upregulated genes involved in ALT mechanism [133]. Suv39h1 mediates heterochromatin formation in pericentric and telomeric regions by trimethylation of lysine 9 of histone 3 (H3K9me3).…”

Section: Epigenetic Regulation Of Tmmsmentioning

confidence: 99%

Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas

Naderlinger

Holzmann

2017

Genes

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High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas. Furthermore, we present new evidence for epigenetic mechanisms (EMs) involved in regulation of ALT and TA with special emphasis on human diffuse gliomas as potential therapeutic drug targets. We discuss the role of TMM associated telomeric chromatin factors such as DNA and histone modifying enzymes and non-coding RNAs including microRNAs and long telomeric TERRA transcripts.

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“…As expected, clonal chromosomal aberrations induced by c-Myc overexpression were found in c-Myc/ wt leukemias of about one-third of primary recipients and in more than 80% of secondary recipients [79]. Notably, leukemias that arose in c-Myc/Suv39h1 -null mice were chromosomally stable, demonstrating that reduced H3K9 trimethylation due to lack of Suv39h1 rather protects leukemic cells from the development of CIN.…”

Section: Epigeneticsmentioning

confidence: 57%

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

Vajen

Thomay

Schlegelberger

2013

Cancers

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Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.

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Histone methyltransferase Suv39h1 deficiency prevents Myc‐induced chromosomal instability in murine myeloid leukemias

Cited by 9 publications

References 30 publications

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

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