DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction

Bröske, Ann-Marie; Vockentanz, Lena; Kharazi, Shabnam; Huska, Matthew R.; Mancini, Elena; Scheller, Marina; Kuhl, Christiane; Enns, Andreas; Prinz, Marco; Jaenisch, Rudolf; Nerlov, Claus; Leutz, Achim; Andrade‐Navarro, Miguel A.; Jacobsen, Sten Eirik W.; Rosenbauer, Frank

doi:10.1038/ng.463

Cited by 419 publications

(387 citation statements)

References 48 publications

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“…For example, differentiation-associated genes are methylated in mouse and human hematopoietic progenitor cells and become demethylated during differentiation (Ji et al, 2010;Bocker et al, 2011). A functional role of DNA methylation in the differentiation of adult progenitor cells is further supported by the observation that hematopoietic stem cells from mice with reduced DNA methyltransferase 1 activity failed to suppress key differentiation genes and lost their ability to differentiate into lymphoid progeny (Broske et al, 2009). While the same study also revealed a therapeutic potential of global DNA hypomethylation for restricting the selfrenewal capacity of leukemia stem cells, the data clearly demonstrates that DNA methylation is required to protect normal hematopoietic stem cells from lineage restriction.…”

Section: Epigenetic Side Effects Of Global Dna Demethylationmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Section: Epigenetic Side Effects Of Global Dna Demethylationmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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“…Thus, it is possible that the suppressive effects of miR-150 in MLL-AF9-transformed cells are mediated through subsets of these networks. We compared our gene expression profiles with 2 datasets comparing murine MLL LSC with HSC or GMP cells (36) with the expression of selected HSC and myeloid progenitor signature genes (37). We found that ectopic expression of miR-150 primarily affects genes that are enriched in HSCs and often upregulated in LSCs instead of GMPs.…”

Section: Mir-150 Transduction Into Mll-af9 Cells Significantly Altersmentioning

confidence: 99%

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Bousquet

Zhuang

et al. 2013

Molecular Cancer Research

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The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in mixed-lineage leukemia (MLL). In this study, miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using MLL-AF9-transformed cells, we demonstrate that ectopic expression of miR-150 inhibits blast colony formation, cell growth, and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in MLL-AF9-transformed cells completely blocked the development of myeloid leukemia in transplanted mice. Furthermore, gene expression profiling revealed that miR-150 altered the expression levels of more than 30 "stem cell signature" genes and many others that are involved in critical cancer pathways. In addition to the known miR-150 target Myb, we also identified Cbl and Egr2 as bona fide targets and shRNA-mediated suppression of these genes recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression.In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes.Implications: These data establish new, key players for the development of therapeutic strategies to treat MLL-AF9-related leukemia. Mol Cancer Res; 11(8); 912-22. Ó2013 AACR.

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“…These somatic mutations accumulated in a cell type with a methylation signature resembling an embryonic stem cell-possibly an HSC (Broske et al 2009). If we assume that it took 115 years for all of the roughly 450 somatic mutations to accumulate in the nonrepetitive genome of one HSC, then with a constant mutation rate, this amounts to about four mutations per year or about three mutations per division, given that HSCs self-renew once every 25-50 wk (Catlin et al 2011).…”

Section: Somatic Mutations Routinely Occur In the Blood Genomementioning

confidence: 99%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

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DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction

Cited by 419 publications

References 48 publications

Epigenetic cancer therapy: rationales, targets and drugs

Epigenetic cancer therapy: rationales, targets and drugs

miR-150 Blocks MLL-AF9–Associated Leukemia through Oncogene Repression

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

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