Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells

Guryanova, Olga A.; Lieu, Yen K.; Garrett-Bakelman, Francine E.; Spitzer, Barbara; Glass, Jacob L.; Shank, Kaitlyn; Martinez, Ana Belen Valencia; Rivera, Sharon A.; Durham, Benjamin H.; Rapaport, Franck; Keller, Matthew D.; Pandey, Suveg; Bastian, Lennart; Tovbin, Daniel; Weinstein, Abby R; Teruya‐Feldstein, Julie; Abdel‐Wahab, Omar; Santini, Valeria; Mason, Christopher E.; Melnick, Ari; Mukherjee, Siddhartha; Levine, Ross L.

doi:10.1038/leu.2015.358

Cited by 59 publications

(60 citation statements)

References 51 publications

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“…Considering that most of the reported DNMT3A mutations in human myeloid neoplasms are heterozygous (1, 2), we observed a transplantable AML phenotype in Dnmt3a R878H/WT heterozygous animals whereas homozygous mice showed growth inhibition and died soon after birth. The leukemia phenotype in mice bore some similarities to that in a Dnmt3a −/− murine model (23). Our results showed that leukemic LSKs were composed mostly of LRPs and contained leukemia-initiating cells.…”

Section: Discussionsupporting

confidence: 53%

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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Section: Discussionsupporting

confidence: 53%

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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“…Furthermore, analysis of all expressed genes failed to demonstrate any trends in expression that correlated with differences in methylation in promoters or gene bodies (Figures 5E, S5J). Importantly, specific genes previously reported to be dysregulated by the overexpression of DNMT3A R882H and/or the loss of Dnmt3a in mice (Guryanova et al, 2016; Jeong et al, 2013; Rau et al, 2016) were not different between the primary human DNMT3A R882H/C and DNMT3A WT AMLs in this study, or in the TCGA dataset (Figures 5F, S5K), demonstrating that DNMT3A R882H/C AMLs do not have an easy-to-define expression phenotype, despite the presence of significant differences in methylation at some linked promoters.…”

Section: Resultsmentioning

confidence: 99%

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Spencer

Russler‐Germain

Ketkar

et al. 2017

Cell

188

193

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Summary DNMT3A mutations occur in ~25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by ~80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing, and was essentially absent in AMLs with DNMT3AR882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.

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“…Jankowska et al reported that 25% of patients with sAML arising from previous CMML harbored DNMT3A mutations, possibly suggesting a higher probability of evolution to AML for CMML patients with DNTM3A mutations; however, this study investigated a small cohort (Jankowska et al 2011) and larger studies are needed. As described for AML, DNMT3A mut CMML is reported to display significantly reduced DNA methylation, mainly at intergenic and intronic regions (Meldi et al 2015) and low-DNA methylation levels are also reported in a Dnmt3a-null MDS/ MPN mouse model (Guryanova et al 2015). However, whether this methylation pattern impacts the disease phenotype and eventually the prognosis of MDS/MPN patients is still unknown, and more studies are required to answer these important questions.…”

Section: Dnmt3a Mutations In Myeloproliferative Neoplasms and Myelodymentioning

confidence: 93%

DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

151

108

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DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies. Here, we discuss the biology of DNMT3A and its role in controlling hematopoietic stem cell fate decisions. In addition, we review how mutant DNMT3A may contribute to leukemogenesis and the clinical relevance of DNMT3A mutations in hematologic cancers. DNA methylation is an epigenetic modification involved in key cellular processes such as transcriptional repression, genomic imprinting, and the suppression of repetitive elements. The first suggestion of a link between DNA methylation and cancer was the observation that human cancers tend to display global hypomethylation compared with normal controls (Feinberg and Vogelstein 1983). Subsequently, the field switched attention to focally hypermethylated regions with the hypothesis that epigenetic silencing of tumor suppressor genes through promoter hypermethylation would drive gene silencing, obviating the need for genetic inactivation of these pathways (Jones and Laird 1999). Investigators then began looking for possible genes/pathways responsible for the observed methylation changes.The deposition and maintenance of DNA methyl marks is orchestrated by DNA methyltransferases. In mammals, three genes encoding proteins with DNA methyltransferase activity have been identified: DNMT1, DNMT3A, and DNMT3B (Okano et al. 1998). DNMT3A and DNMT3B proteins are responsible for establishing the patterns of DNA methylation early in embryogenesis through de novo methylation of unmethylated CpG sites , and DNMT1 maintains such patterns throughout cell division by targeting hemimethylated 6 These authors contributed equally to this work.

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Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells

Cited by 59 publications

References 51 publications

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

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

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

DNMT3A in Leukemia

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