News - DNMT3A R882H - LARVOL VERI

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations. (PubMed, Nat Commun)

Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

8 days ago

Journal

DNMT3A (DNA methyltransferase 1) • DNMT3B (DNA Methyltransferase 3 Beta)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

XPO1 inhibition displays anti-leukemia efficacy against DNMT3A-mutant acute myeloid leukemia via downregulating glutathione pathway. (PubMed, Ann Hematol)

In conclusion, our work reveals that selinexor displays anti-leukemia efficacy against DNMT3AR882H AML via downregulating glutathione pathway. Combination of selinexor and BSO provides novel therapeutic strategy for AML treatment.

1 month ago

Journal • IO biomarker

DNMT3A (DNA methyltransferase 1) • XPO1 (Exportin 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

Xpovio (selinexor)

3ms

Rapid and accurate remethylation of DNA in Dnmt3a-deficient hematopoietic cells with restoration of DNMT3A activity. (PubMed, Sci Adv)

Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3a marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.

3 months ago

Journal

DNMT3A (DNA methyltransferase 1) • DNMT3B (DNA Methyltransferase 3 Beta)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

6ms

DNMT3A R882H Exhibits Greater Inflammatory Potential Than R882C in Primary Hematopoietic Stem and Progenitor Cell Knock-in Model and Population Data (ASH 2023)

In Cox proportional hazards models controlling for basic demographics (N = 451K) or demographics plus cardiovascular-relevant covariates (N = 390K), we found that R882H but not R882C was associated with significantly greater incidence of heart failure and of a composite measure consisting of death or coronary artery disease (Figure 1B). In conclusion, our study found evidence in experimental models and patient data that DNMT3A R882H may pose a greater risk for inflammatory phenotypes than R882C.

6 months ago

Clinical

DNMT3A (DNA methyltransferase 1) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • S100A8 (S100 Calcium Binding Protein A8) • S100A9 (S100 Calcium Binding Protein A9)

DNMT3A R882H • DNMT3A R882

6ms

Gene Correction of DNMT3A:R882H in Primary Human AML Demonstrates That This Mutation Is Not Required for Disease Maintenance, but Is Associated with Increased Leukemia Stem Cell Frequency (ASH 2023)

In summary, our work demonstrates a novel CRISPR/Cas9 approach to dissect the contribution of individual somatic lesions in human leukemia. The precise correction of single lesions while leaving co-occurring mutations intact allows us to perform controlled, functional genetic experiments on primary human AML. Here, we employ this approach to dissect the contribution of DNMT3A mutations to leukemia initiation and maintenance.

6 months ago

Clinical

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

6ms

Inactivation of DNA Polymerase Theta (PolΘ) Is Synthetic Lethal in DNMT3A Mutated Myeloid Malignancies – Potential Clinical Applications (ASH 2023)

DNMT3A mutations promote resistance to anthracyclines (including daunorubicin, the component of standard "7+3" induction therapy), interferon alpha, and ABL1 kinase inhibitor imatinib...The combination of Polθis + quizartinib and Polθis + etoposide completely eradicated clonogenic activity of these cells while Polθis + cytarabine and Polθis + azacytidine exerted modest and weak effects, respectively, when compared to individual compound treatments...Median survival time of the mice will be recorded. Altogether, we discovered that Polθ protects OTK-positive DNMT3A-deficient myeloid malignant cells from the toxic effects of DSBs and identified Polθ as a novel therapeutic target.

6 months ago

Clinical • Synthetic lethality

FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • STING (stimulator of interferon response cGAMP interactor 1) • CHEK1 (Checkpoint kinase 1) • RAD52 (RAD52 Homolog DNA Repair Protein)

DNMT3A mutation • JAK2 V617F • DNMT3A R882H • DNMT3A R882

imatinib • cytarabine • azacitidine • etoposide IV • Vanflyta (quizartinib) • daunorubicin

7ms

Base Editor Scanning Reveals Activating Mutations of DNMT3A. (PubMed, ACS Chem Biol)

Notably, these mutations are still activating in the context of a heterozygous R882H mutation. Altogether, we showcase the utility of base editor scanning for discovering functional regions of target proteins.

7 months ago

Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

8ms

Diversity of DNMT3A, TET2, and ASXL1 Gene Variants in Patients With Acute Myeloid Leukemia (AML) (SOHO 2023)

There is a great diversity of possible genetic alterations in DNMT3A, TET2, and ASXL1 genes, which requires detailed investigation. Further studies in dynamics will evaluate their prognostic impacts in AML patients.

8 months ago

Clinical

DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

DNMT3A mutation • ASXL1 mutation • TET2 mutation • DNMT3A R882H • DNMT3A R882

9ms

DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming. (PubMed, J Transl Med)

Taken together, our data showed that DNMT3A mutation caused NAMPT overexpression to induce the reprogramming of NAM-NAD metabolism and contribute to abnormal proliferation, which provided a potential direction for targeted therapy at the metabolic level in AML with DNMT3A mutation.

9 months ago

Journal

DNMT3A (DNA methyltransferase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • NAMPT (Nicotinamide Phosphoribosyltransferase)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882 • NAMPT overexpression

daporinad (APO866)

1year

DNMT3A R882H mutation promotes acute leukemic cell survival by regulating glycolysis through the NRF2/NQO1 axis. (PubMed, Cell Signal)

Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment of AML patients carrying a DNMT3A R882H mutation.

1 year ago

Journal

DNMT3A (DNA methyltransferase 1) • NQO1 (NAD(P)H dehydrogenase, quinone 1)

DNMT3A mutation • NFE2L2 mutation • DNMT3A R882H • DNMT3A R882 • NQO1 mutation

daunorubicin

over1year

Venetoclax and azacitidine induced cytogenetic response in an elderly patient with IDH2- and DNMT3A-mutated refractory acute myeloid leukemia (PubMed, Rinsho Ketsueki)

He received a reduced dose of idarubicin and cytarabine therapy. Even 9 months after starting VEN+AZA, the patient is still alive and healthy without AML recurrence. Thus, VEN+AZA therapy may be highly effective for treating IDH2- and DNMT3A-mutated AML in elderly patients.

over 1 year ago

Journal

IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • IDH2 R172K • DNMT3A R882H • DNMT3A R882 • IDH2 R172

Venclexta (venetoclax) • cytarabine • azacitidine • idarubicin hydrochloride

over1year

Acute Myeloid Leukemia with CEBPA Mutation: Next-Generation Sequencing-Based Computational Approach For Enhancing the Diagnosis of Patients with Potential Germline CEBPA Mutated Predisposition (USCAP 2023)

Recognizing and referring patients with possible germline mutations for appropriate genetic evaluation and testing provides insight into best patient care strategies along with education and testing opportunities for family members. Leukemia based NGS panels may aid as screening tools for detecting potential pathogenic germline variants.

over 1 year ago

Clinical • Next-generation sequencing

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • KMT2C (Lysine Methyltransferase 2C) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • CD36 (thrombospondin receptor) • MSH3 (MutS Homolog 3) • GATA2 (GATA Binding Protein 2) • PHF6 (PHD Finger Protein 6) • BCORL1 (BCL6 Corepressor Like 1)

NRAS Q61 • CEBPA mutation • NRAS G13 • NRAS Q61L • DNMT3A R882H • IDH1 R132 • NRAS G13D • NRAS G13R • IDH2 R140Q • DNMT3A R882 • NPM1 W288

FoundationOne® Heme CDx

over1year

Evaluating Stem Cells to Predict Post-Transplant Relapse in the Myelodysplastic Syndromes (ASH 2022)

Validation of this assay in larger cohorts promises to yield a tool to identify patients who may benefit from early post-transplant interventions to forestall relapse. We also demonstrate how this assay can reveal novel insights into human disease HSC biology.

over 1 year ago

IO biomarker

TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • DDX41 (DEAD-Box Helicase 41)

TP53 mutation • ASXL1 mutation • DDX41 mutation • DNMT3A R882H • IDH2 R140Q • TP53 Y220C • DNMT3A R882

over1year

A Murine Model Harboring Cooperating DNMT3A and SF3B1 Mutations Phenocopies SF3B1 Driven Myelodysplastic Syndrome (ASH 2022)

Taken together, our in vivo and transcriptomic studies show that Sf3b1 point mutations are a stronger driver of stem cell self-renewal and gene expression than Dnmt3a mutations in Sf3b1/Dnmt3a mutant HSPCs. These findings suggest that agents that interfere with the DNA damage response, cell cycle regulation, or spliceosome function may more effectively target SF3B1 and SF3B1/DNMT3A mutant HSCs in patients with MDS.

over 1 year ago

Preclinical

DNMT3A (DNA methyltransferase 1) • SF3B1 (Splicing Factor 3b Subunit 1)

DNMT3A mutation • SF3B1 mutation • SF3B1 K700E • DNMT3A R882H • DNMT3A R882

over1year

DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway. (PubMed, Cell Commun Signal)

Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. Video abstract.

over 1 year ago

Journal

DNMT3A (DNA methyltransferase 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2) • NQO1 (NAD(P)H dehydrogenase, quinone 1)

DNMT3A mutation • NFE2L2 mutation • DNMT3A R882H • DNMT3A R882

daunorubicin

over1year

Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases. (PubMed, Curr Opin Struct Biol)

Given the role of DNMT3A in establishing de novo DNA methylation during development, it is this CpG methylation and deamination that provide the major mutagenic impetus in the DNMT3A gene itself, including the R882H dominant-negative substitution associated with two diseases: germline mutations in DNMT3A overgrowth syndrome, and somatic mutations in clonal hematopoiesis that can initiate acute myeloid leukemia. We discuss recent developments in therapeutics targeting DNMT1, the role of noncatalytic isoform DNMT3B3 in regulating de novo methylation by DNMT3A, and structural characterization of DNMT3A in various configurations.

over 1 year ago

Review • Journal

DNMT3A (DNA methyltransferase 1) • DNMT1 (DNA methyltransferase 1) • DNMT3B (DNA Methyltransferase 3 Beta)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

almost2years

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS. (PubMed, Blood)

Single-cell-RNA-seq analysis of CD3+ T-cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance, thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

almost 2 years ago

Journal

DNMT3A (DNA methyltransferase 1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TBX21 (T-Box Transcription Factor 21) • GATA3 (GATA binding protein 3)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

2years

Preferential self-interaction of DNA methyltransferase DNMT3A subunits containing the R882H cancer mutation leads to dominant changes of flanking sequence preferences. (PubMed, J Mol Biol)

As the subunits at the RD interface form the active centers of the DNMT3A tetramer, R882H specific flanking sequence preferences of DNMT3A were observed in mixed tetrameric complexes containing WT and R882H subunits, and they are not diluted by the "averaged" effects of mixed or WT interfaces. Hence, R882H has a dominant effect on the flanking sequence preferences and other catalytic properties of DNMT3A in samples containing WT and R882H subunits, which may explain its pathogenic effect in heterozygous state.

2 years ago

Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

2years

Pseudo-mutant P53 is a unique phenotype of DNMT3A-mutated pre-leukemia. (PubMed, Haematologica)

Our observations shed light upon a possible targetable P53 dysfunction in human preLHSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.

2 years ago

Journal

TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1)

TP53 mutation • DNMT3A mutation • DNMT3A R882H • DNMT3A R882

over2years

DNMT3A with Leukemia-Associated R882 Mutations Promotes Fitness Advantage through Functional Heterogeneity within HSCs (ASH 2021)

Collectively, these data suggest that the DNMT3A R882 mutations endow normal HSCs with phenotypic heterogeneity yielding a population of cells with variable stem cell function, some of which may have higher fitness thus accelerating clonal evolution towards malignancy. These findings will be built upon in future experiments aiming to identify underlying molecular mechanisms and to improve our understanding of the pathophysiology and prognostication of clonal hematopoiesis.

over 2 years ago

DNMT3A (DNA methyltransferase 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

almost3years

Effect of DNMT3A variant allele frequency and double mutation on clinicopathologic features of patients with de novo AML. (PubMed, Blood Adv)

In multivariable analyses performed in NK patients who received standard induction chemotherapy, presence of 2 DNMT3A mutations (hazard ratio [HR] = 3.192; P = .038) and SCT in first complete remission (HR = 0.295; P = .001) independently affected EFS; increasing marrow blast percentage (HR = 1.026; P = .025), high DNMT3A VAF (HR = 3.003; P = .010), and 2 DNMT3A mutations (HR = 4.816; P = .020) had independent effects on OS. These data support the adverse prognostic significance of DNMT3AHIGH reveal a novel association between 2 concomitant DNMT3A mutations and inferior outcome in DNMT3A-mutated de novo AML with a NK.

almost 3 years ago

Clinical • Journal

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

NPM1 mutation • DNMT3A mutation • DNMT3A R882H • DNMT3A R882

almost3years

Study on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation. (PubMed, Front Immunol)

It relieved the inhibitory effect of DNMT3A mutation, promoted the phenotypic recovery of the co-cultured macrophages, eliminated resistance, and regulated the immune microenvironment. Thus, resistin may serve as an ancillary drug for patients with DNMT3A-mutated AML.

almost 3 years ago

Journal • IO biomarker

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

almost3years

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A. (PubMed, Biomolecules)

CDK1 selective inhibitor CGP74514A (CGP) and the pan-CDK inhibitor flavopiridol (FLA) arrested OCI-AML3 cells in the G2/M phase, and induced cell apoptosis...Moreover, the combined application of CDK1 inhibitor and traditional chemotherapy drugs synergistically inhibited proliferation and induced apoptosis of OCI-AML3 cells. In conclusion, this study highlights CDK1 overexpression as a pathogenic factor and a potential therapeutic target for DNMT3A mutation-related AML.

almost 3 years ago

Journal

DNMT3A (DNA methyltransferase 1) • CD163 (CD163 Molecule) • CDK1 (Cyclin-dependent kinase 1)

DNMT3A mutation • DNMT3A R882H • CDK1 overexpression • DNMT3A R882

alvocidib (DSP-2033)

almost3years

[VIRTUAL] TRACKING CLONAL HEMATOPOIESIS IN PATIENTS WITH CLASSICAL HODGKIN LYMPHOMA (EHA 2021)

Conclusion CH can be observed in the cHL tissue, can originate the tumor clone and can propagate to large part of its microenvironment. Considering that both tumor cells and the microenvironment supporting its growth play key roles in cHL pathogenesis, CH might contribute to the development of this lymphoma and influence its prognosis.

almost 3 years ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D) • SOCS1 (Suppressor Of Cytokine Signaling 1) • STAT6 (Signal transducer and activator of transcription 6)

TP53 mutation • KRAS mutation • NPM1 mutation • DNMT3A mutation • DNMT3A R882H • DNMT3A R882 • KRAS G60D • SOCS1 mutation

almost3years

AML-Associated Mutations in DNA Methyltransferase DNMT3A. (PubMed, Biochemistry (Mosc))

The impact of R882H and less common missense mutations on the DNMT3A activity toward model DNA substrates and in cancer cell lines is discussed together with the underlying molecular mechanisms. Understanding general features of these mechanisms will be useful for further development of novel approaches for early diagnostics of hematologic diseases and personalized cancer therapy.

almost 3 years ago

Review • Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

over3years

Analysis of non-leukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant pre-leukemic clones. (PubMed, Int J Cancer)

The presence of leukemia-specific mutations in these non-leukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long-term cure.

over 3 years ago

Journal • IO biomarker

NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CD38 (CD38 Molecule) • CD34 (CD34 molecule)

NRAS mutation • DNMT3A mutation • DNMT3A R882H • DNMT3A R882

over3years

Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia. (PubMed, Biomolecules)

There was a complete loss of DNA-binding affinity for R45W located in the AdoMet binding region and for R146H. Dnmt3a mutants studied in vitro suggest functional impairment of DNMT3A during pathogenesis.

over 3 years ago

Clinical • Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

over3years

Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. (PubMed, Nat Commun)

Consistently, in vitro methylation analyses indicate that the R882H mutation compromises the enzymatic activity, CpG specificity and flanking sequence preference of DNMT3A. Together, this study uncovers multiple defects of DNMT3A caused by the R882H mutation in AML.

over 3 years ago

Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

over3years

Clonal haematopoiesis and risk of acute myeloid leukemia. (PubMed, Haematologica)

Our findings are consistent with published evidence that detection of clonal mutations ≥0.01 variant allele fraction identifies individuals at increased risk for acute myeloid leukemia. Further study of larger populations, mutations co-occurring within the same pre-leukemic clone and other risk factors (lifestyle, epigenetics, etc.), are still needed to fully elucidate the risk conferred by low-frequency clonal hematopoiesis in asymptomatic adults.

over 3 years ago

Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882

almost4years

DNMT3A R882H mutation in acute myeloid leukemia cell line SET-2. (PubMed, Leuk Res)

No abstract available

almost 4 years ago

Journal

DNMT3A (DNA methyltransferase 1)

DNMT3A mutation • DNMT3A R882H • DNMT3A R882