The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers

Russler‐Germain, David A.; Spencer, David H.; Young, Margaret A.; Lamprecht, Tamara; Miller, Christopher A.; Fulton, Robert S.; Meyer, Matthew R.; Erdmann-Gilmore, Petra; Townsend, R. Reid; Wilson, Richard K.; Ley, Timothy J.

doi:10.1016/j.ccr.2014.02.010

Cited by 393 publications

(407 citation statements)

References 37 publications

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“…It remains unknown whether DNMT3a loss is an oncogenic event; however, it likely plays a central role in genetically diverse cancer cells to proliferate and remain viable under hypoxic conditions. Based on these observations and those of others, we propose that DNMT3a functions as a gatekeeper tumor suppressor (35,36) further genetic studies will be necessary to clearly demonstrate biallelic-inactivating mutations of DNMT3a in primary tumors. Nonetheless, the data shown here underlie the fundamental role of epigenetic reprogramming in the attainment of the hypoxic cancer cell phenotype.…”

Section: Discussionsupporting

confidence: 59%

“…that DNMT3a is a tumor-suppressor gene and that its mutation, or mRNA down-regulation, contributes to reducing global DNMT3a methyltransferase activity (35,36). Currently, a key challenge is to link aberrant methylation profiles commonly observed in malignant lesions, including alterations in the DNMT3a epigenetic program, to genes that directly promote the tumorigenic phenotype.…”

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confidence: 99%

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DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

Lachance

Uniacke

Audas

et al. 2014

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

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Epigenetic regulation of gene expression by DNA methylation plays a central role in the maintenance of cellular homeostasis. Here we present evidence implicating the DNA methylation program in the regulation of hypoxia-inducible factor (HIF) oxygensensing machinery and hypoxic cell metabolism. We show that DNA methyltransferase 3a (DNMT3a) methylates and silences the HIF-2α gene (EPAS1) in differentiated cells. Epigenetic silencing of EPAS1 prevents activation of the HIF-2α gene program associated with hypoxic cell growth, thereby limiting the proliferative capacity of adult cells under low oxygen tension. Naturally occurring defects in DNMT3a, observed in primary tumors and malignant cells, cause the unscheduled activation of EPAS1 in early dysplastic foci. This enables incipient cancer cells to exploit the HIF-2α pathway in the hypoxic tumor microenvironment necessary for the formation of cellular masses larger than the oxygen diffusion limit. Reintroduction of DNMT3a in DNMT3a-defective cells restores EPAS1 epigenetic silencing, prevents hypoxic cell growth, and suppresses tumorigenesis. These data support a tumor-suppressive role for DNMT3a as an epigenetic regulator of the HIF-2α oxygensensing pathway and the cellular response to hypoxia.

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Section: Discussionsupporting

confidence: 59%

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confidence: 99%

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

Lachance

Uniacke

Audas

et al. 2014

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

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“…Although mouse Dnmt3a R878H (corresponding to human R882H) mutant protein can still interact with wild-type Dnmt3a and Dnmt3b, co-expression of wild-type and mutant form in murine embryonic stem (ES) cells led to inhibition of the wild-type DNA methylation ability, consistent with dominant-negative effect of DNMT3A R882H mutations [25]. Moreover, DNMT3A R882H mutant was shown to inhibit wild-type de novo methylation activity by disrupting the formation of its functional tetramers [26], further confirming the dominant-negative role of this mutant.…”

Section: Dnmt3amentioning

confidence: 76%

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

Kunimoto

Nakajima

2017

Int J Hematol

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“…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)(12)(13).…”

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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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The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers

Cited by 393 publications

References 37 publications

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

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

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