Dnmt3a is essential for hematopoietic stem cell differentiation

Challen, Grant A.; Sun, Deqiang; Jeong, Mira; Luo, Min; Jelı́nek, Jaroslav; Berg, Jonathan S.; Bock, Christoph; Vasanthakumar, Aparna; Gu, Hongcang; Xi, Yuanxin; Liang, Shoudan; Lu, Yao; Darlington, Gretchen J.; Meissner, Alexander; Issa, Jean–Pierre J.; Godley, Lucy A.; Li, Wei; Goodell, Margaret A.

doi:10.1038/ng.1009

Cited by 945 publications

(669 citation statements)

References 47 publications

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“…7B). Consistent with the published observation that dif- (4,24,25), we found that an intergenic region in the proximity of the Iqgap2 locus was substantially hypomethylated in KO cells (Fig. 7B).…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Massupporting

confidence: 81%

“…S1D). Second, the differentially methylated regions identified in Dnmt3a-null cells showed substantial hyper-as well as hypomethylation at a variety of genomic regions, with very little correlation between changes in methylation and differential gene expression in the absence of Dnmt3a in both mouse and human cells (4,24,25). These observations suggest the existence of both direct and indirect effects due to the loss of Dnmt3a, and potentially also the existence of DNMT3A activities that are independent of its DNA catalytic activity (26), similar to what has been described for the catalytically inactive DNMT3L (27), some of the DNMT3B isoforms (28), and even for the TET family of DNA-modifying enzymes (29,30).…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

“…The DNA methylation status of different cell types, including cells of the hematopoietic lineage, with or without Dnmt3a, has been previously studied (23)(24)(25): First, HSCs lacking Dnmt3a showed global 5mC levels that were comparable to those of control cells, with a very modest number of differentially methylated regions (24). In agreement with these findings, we found that overall levels of genomic 5mC were not significantly different in WT and KO mast cells, despite a trend toward slightly diminished levels in KO cells (Fig.…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

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Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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Section: Dysregulated Dna Methylation Activity Leads To Increased Massupporting

confidence: 81%

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

See 1 more Smart Citation

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Careful genotypephenotype correlations suggest that patients manifest DNMT3A mutations in preleukemic hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs), which exhibit a competitive advantage over normal HSCs. Because these mutations occur at a very early stage among genetic abnormalities, they are likely involved in the development of leukemia (7,8).Functionally, the DNMT3A R882 mutation might disrupt epigenetic regulation. This kind of DNMT3A mutation confers reduced methyltransferase activity and promotes the possibility of dominant-negative consequences compared with the wild-type (WT) allele (2, 9, 10).…”

mentioning

confidence: 99%

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

Dai

Wang

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin − Sca1 + cKit + cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G 2 /M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a R878H/WT mice.have been identified in a subset of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), with DNMT3A R882 being the hotspot (1-4). Clinical features of most AML cases with DNMT3A mutations include preferential involvement of a monocytic lineage (AML-M4 and -M5 subtypes), thrombocytosis, onset at a relatively old age, and poor prognosis (2, 5, 6). Careful genotypephenotype correlations suggest that patients manifest DNMT3A mutations in preleukemic hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs), which exhibit a competitive advantage over normal HSCs. Because these mutations occur at a very early stage among genetic abnormalities, they are likely involved in the development of leukemia (7,8).Functionally, the DNMT3A R882 mutation might disrupt epigenetic regulation. This kind of DNMT3A mutation confers reduced methyltransferase activity and promotes the possibility of dominant-negative consequences compared with the wild-type (WT) allele (2, 9, 10). Moreover, the DNMT3A mutation causes aberrant DNA hypomethylation and up-regulates a series of target genes involved in AML pathogenesis (11-13).In vivo animal tests have shown that the Dnmt3a gene plays an essential role in hematopoiesis regulation. Dnmt3a −/− HSCs expand remarkably, but their differentiation is inhibited when Dnmt3a is conditionally inactivated in the murine hematopoietic system; this phenomenon is consistent with a preleukemic state (7). Moreover, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 y and were diagnosed with a spectrum of malignancies similar to those observed in patients carrying DNMT3A mutations, including MDS, AML, primary myelofibrosis, and ALL, suggesting that Dnmt3a functions as a tumor suppressor (7). With a second hit of mutations in various genes such as N-RAS, C-KIT, or FLT3 in Dnmt3a −/− mice, Dnmt3a deletion induces leukemic transformation (14, 15). Although these results indicate a major role of Dnmt3a deletion in facilitating the development of leukemia, the in vivo roles of DNMT3A mutants in leukemogenesis still need to be addressed. In our previous work, b...

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“…There is considerable heterogeneity in genetic mutations among patients with MDS that may explain the diversity of clinical presentations that differ in the numbers and depths of cytopenias, risks toward progression to acute myeloid leukemia (AML), responses to treatment, and survival times [5][6][7][8]. Gene mutations affecting epigenetic chemical modifications, such as mutations in TET2 and DNMT3A, are among the most common in MDS [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cogle

Scott

Boyd³

2015

The Oncologist

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The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with .30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.

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Dnmt3a is essential for hematopoietic stem cell differentiation

Cited by 945 publications

References 47 publications

Dnmt3a restrains mast cell inflammatory responses

Dnmt3a restrains mast cell inflammatory responses

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

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