Reference Detail

Ref Type

Journal Article

PMID

(31164355)

Authors

Lu R, Wang J, Ren Z, Yin J, Wang Y, Cai L, Wang GG

Title

A Model System for Studying the DNMT3A Hotspot Mutation (DNMT3AR882) Demonstrates a Causal Relationship between Its Dominant-Negative Effect and Leukemogenesis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	79	14	2019 Jul 15	3583-3594	Cancer Res

URL

Abstract Text

Mutation of DNA methyltransferase 3A at arginine 882 (DNMT3AR882mut) is prevalent in hematologic cancers and disorders. Recently, DNMT3AR882mut has been shown to have hypomorphic, dominant-negative, and/or gain-of-function effects on DNA methylation under different biological contexts. However, the causal role for such a multifaceted effect of DNMT3AR882mut in leukemogenesis remains undetermined. Here, we report TF-1 leukemia cells as a robust system useful for modeling the DNMT3AR882mut-dependent transformation and for dissecting the cause-effect relationship between multifaceted activities of DNMT3AR882mut and leukemic transformation. Ectopic expression of DNMT3AR882mut and not wild-type DNMT3A promoted TF-1 cell transformation characterized by cytokine-independent growth, and induces CpG hypomethylation predominantly at enhancers. This effect was dose dependent, acted synergistically with the isocitrate dehydrogenase 1 (IDH1) mutation, and resembled what was seen in human leukemia patients carrying DNMT3AR882mut. The transformation- and hypomethylation-inducing capacities of DNMT3AR882mut relied on a motif involved in heterodimerization, whereas its various chromatin-binding domains were dispensable. Mutation of the heterodimerization motif that interferes with DNMT3AR882mut binding to endogenous wild-type DNMT proteins partially reversed the CpG hypomethylation phenotype caused by DNMT3AR882mut, thus supporting a dominant-negative mechanism in cells. In mice, bromodomain inhibition repressed gene-activation events downstream of DNMT3AR882mut-induced CpG hypomethylation, thereby suppressing leukemogenesis mediated by DNMT3AR882mut. Collectively, this study reports a model system useful for studying DNMT3AR882mut, shows a requirement of the dominant-negative effect by DNMT3AR882mut for leukemogenesis, and describes an attractive strategy for the treatment of leukemias carrying DNMT3AR882mut. SIGNIFICANCE: These findings highlight a model system to study the functional impact of a hotspot mutation of DNMT3A at R882 in leukemia.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
DNMT3A	R882C	missense	loss of function	DNMT3A R882C lies within the SAM-dependent MTase C5-type domain of the Dnmt3a protein (UniProt.org). R882C results in a loss of Dnmt3a protein function as indicated by genomic hypomethylation (PMID: 32015320, PMID: 31164355), which leads to altered gene expression profiles, reduced apoptosis, increased proliferation, cell transformation, and activation of hematopoietic stem cells in culture (PMID: 27010239, PMID: 31164355, PMID: 30245403, PMID: 32015320).
DNMT3A	R882H	missense	loss of function	DNMT3A R882H lies within the SAM-dependent MTase C5-type domain of the Dnmt3a protein (UniProt.org). R882H results in protein stability similar to wild-type Dnmt3a in culture (PMID: 34429321), but disrupts the tetramerization ability of the Dnmt3a protein, resulting in reduced DNA binding affinity and altered catalytic activity in in vitro assays (PMID: 22722925), disrupts Tp53 inhibition of methylation (PMID: 31640986), results in hypomethylation, cytokine-independent growth, increased cell proliferation and impaired differentiation in cultured cells (PMID: 31164355, PMID: 32015320), and decreased methylation activity in cell culture (PMID: 34429321).
DNMT3A	R882S	missense	loss of function	DNMT3A R882S lies within the SAM-dependent MTase C5-type domain of the Dnmt3a protein (UniProt.org). R882S results in a loss of Dnmt3a protein function, as demonstrated by cytokine-independent growth and hypomethylation in cultured cells (PMID: 31164355).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
DNMT3A R882H NRAS G12D	acute myeloid leukemia	sensitive	I-BET151	Preclinical - Cell line xenograft	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring DNMT3A R882H and NRAS G12D mutations demonstrated reduced proliferation and downregulation of a DNMT3A R882H associated gene expression profile upon I-BET151 treatment in culture, and I-BET151 treatment delayed the onset of leukemia symptoms and improved survival in xenograft mouse models derived from these cells (PMID: 31164355).	31164355
DNMT3A R882H NRAS G12D	acute myeloid leukemia	sensitive	I-BET151 + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, an acute myeloid leukemia cell line xenograft model harboring DNMT3A R882H and NRAS G12D treated with combined I-BET151 and Mekinist (trametinib) demonstrated impaired disease progression and improved survival superior to either therapy alone (PMID: 31164355).	31164355
DNMT3A R882H NRAS G12D	acute myeloid leukemia	sensitive	Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, an acute myeloid leukemia cell line xenograft model harboring DNMT3A R882H and NRAS G12D was sensitive to Mekinist (trametinib), demonstrating impaired disease progression and improved survival (PMID: 31164355).	31164355