DNMT3A Haploinsufficiency Transforms <i>FLT3</i>ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia

Meyer, Sara E.; Qin, Tingting; Muench, David E.; Masuda, Kohei; Venkatasubramanian, Meenakshi; Orr, Emily; Suarez, Lauren; Gore, Steven D.; Delwel, Ruud; Paietta, Elisabeth; Tallman, Martin S.; Fernandez, Hugo F.; Melnick, Ari; Beau, Michelle M. Le; Kogan, Scott C.; Salomonis, Nathan; Figueroa, María E.; Grimes, H. Leighton

doi:10.1158/2159-8290.cd-16-0008

Cited by 79 publications

(70 citation statements)

References 75 publications

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“…The contribution of these Dnmt3a-null HSCs to blood production is minimal, reflecting an imbalance between self-renewal and differentiation driven by loss of DNMT3A (bottom). myeloid cancers (Meyer et al 2016;Yang et al 2016). Taken together, these data strongly indicate that DNMT3A is a haploinsufficient tumor suppressor gene in myeloid leukemias, when cooperating mutations are present.…”

Section: Dnmt3a Mutations and Cancermentioning

confidence: 58%

“…The mutant protein can dimerize with WT DNMT3A, but tetramers, which comprise a substantially more active form of the protein, are not able to form (Holz-Schietinger et al 2012;Russler-Germain et al 2014). The resulting low levels of DNMT3A homotetramers result in a significant reduction of methytransferase activity, providing an explanation for the genome-wide hypomethylation observed in patients with R882 mutations (Cancer Genome Atlas Research 2013;Qu et al 2014;Meyer et al 2016;Yang et al 2016). In addition, the R882 mutant may acquire other deleterious interactions.…”

Section: Dnmt3a Mutations and Cancermentioning

confidence: 99%

“…DNMT3A mut AMLs frequently harbor NPM1 (NPM1 cþ ) and FLT3 mutations, with 60% -80% of DNMT3A mut cases having NPM1 cþ and 30% displaying both NPM1 and FLT3 mutations (Cancer Genome Atlas Research 2013; Gaidzik et al 2013;Gale et al 2015). Although there is evidence that Npm1 cþ /Flt3-ITD mice (Mupo et al 2013) and Dnmt3a mut /Flt3-ITD mice (Meyer et al 2016) develop leukemia with 100% penetrance, no data have been published on Dnmt3a mut / Npm1 cþ mice. It therefore remains unclear whether any of these mutations plays a central role in determining such specific clinical phenotype.…”

Section: Dnmt3a In Leukemiamentioning

confidence: 99%

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DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

152

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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Section: Dnmt3a Mutations and Cancermentioning

confidence: 58%

Section: Dnmt3a Mutations and Cancermentioning

confidence: 99%

Section: Dnmt3a In Leukemiamentioning

confidence: 99%

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DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

152

108

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“…116 A recent study showed that the rescue of DNMT3a expression is accompanied by DNA re-methylation in an AML murine model, indicating that the oncogenic effects of mutant DNMT3a are reversible. 117 Over the past decade, it has become clear that miRNAs can be inactivated by epigenetic mechanisms, such as DNA hypermethylation of CpG sites within CpG islands. Kaiso, which binds to methyl-CpG dinucleotides, could inhibit the expression of miR-31 and promote prostate cancer metastasis.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Mutual regulation of microRNAs and DNA methylation in human cancers

Wang¹,

Wu²,

Claret

2017

Epigenetics

124

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microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper-and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.

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“…These classes of mutations exhibit complex genetic interactions with each other, some showing high propensity of co-occurrence and some showing mutual exclusivity (Chen et al, 2013). Efforts to model the complex mutational landscapes of human AML in animal models have relied largely on mouse genetics by crossing few mutant strains or by introducing the mutant allele by gene transfer, which requires large time- and resource-commitments (Guryanova et al, 2016; Meyer et al, 2016; Shih et al, 2015; Yang et al, 2016). New methods to systematically generate multiple AML animal models with complex mutational landscapes should accelerate the discovery of vulnerabilities shared among AMLs with different genotypes and those that are genotype specific.…”

Section: Introductionmentioning

confidence: 99%

Clonal expansion and myeloid leukemia progression modeled by multiplex gene editing of murine hematopoietic progenitor cells

Shi

Kitano

Jiang

et al. 2018

Experimental Hematology

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Recent advances in next-generation sequencing have identified novel mutations and revealed complex genetic architectures in human hematological malignancies. Moving forward, new methods to quickly generate animal models that recapitulate the complex genetics of human hematological disorders are needed to transform the genetic information to new therapies. Here, we used a ribonucleoprotein-based CRISPR/Cas9 system to model human clonal hematopoiesis of indeterminate potential and acute myeloid leukemia (AML). We edited multiple genes recurrently mutated in hematological disorders, including those encoding epigenetic regulators, transcriptional regulators, and signaling components in murine hematopoietic stem/progenitor cells. Tracking the clonal dynamics by sequencing the indels induced by CRISPR/Cas9 revealed clonal expansion in some recipient mice that progressed to AML initiated by leukemia-initiating cells. Our results establish that the CRISPR/Cas9-mediated multiplex mutagenesis can be used to engineer a variety of murine models of hematological malignancies with complex genetic architectures seen in human disease.

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DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia

Cited by 79 publications

References 75 publications

DNMT3A in Leukemia

DNMT3A in Leukemia

Mutual regulation of microRNAs and DNA methylation in human cancers

Clonal expansion and myeloid leukemia progression modeled by multiplex gene editing of murine hematopoietic progenitor cells

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