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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

ABSTRACT: To investigate the role of PI3K in Dnmt3a loss driven leukemia, bone marrow cells from wildtype or Dnmt3a knockout mice were assayed for differential gene expression.The signaling pathways by which DNMT3A mutations contribute to myeloid transformation are poorly understood. We investigated that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE208435 | GEO | 2022/11/30

REPOSITORIES: GEO

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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway II

Project description:Inhibition of PI3K rescues Dnmt3a loss driven leukemia. The signaling pathways by which DNMT3A mutations contribute to myeloid transformation are poorly understood. We investigated that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase pathway.

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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway II

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Mouse lung tumor tissue: Dnmt3a KO vs. Dnmt3a WT

Project description:Transcriptional profiling of mouse lung tumors comparing Dnmt3a KO/K-ras G12D mutant with Dnmt3a WT/K-ras G12D mutant. The goal is to search for the difference of mRNA abundance between Dnmt3a KO and WT tumors. Two-condition experiment, KO vs. WT tissure. Biological replicates: 12.

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DNMT3A haploinsufficiency predisposes hematopoietic cells to myeloid malignancies

Project description:DNMT3A (which encodes a de novo DNA methyltransferase) is one of the most frequently mutated genes in AML genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins, which could either have dominant negative activities, or cause loss-of-function and haploinsufficiency. We demonstrate that three of these mutants produce truncated, inactive proteins that do not dimerize with wild-type DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation: unmanipulated mice developed myeloid skewing over time, and their stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice spontaneously developed transplantable myeloid malignancies after a long latent period, and three of 12 tumors tested had cooperating mutations in the Ras- MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for DNMT3A alters hematopoiesis, and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.

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The N-terminal region of DNMT3A combines multiple chromatin reading motifs to guide recruitment

Project description:DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns. However, the mechanisms underlying DNMT3A recruitment to and function within different chromatin environments remain unclear. Using a combination of biochemical and structural approaches we find that DNMT3A interacts using multiple interfaces with chromatin; directly binding generic nucleosome features as well as site-specific post-translational histone modifications. The N-terminal region, unique to the DNMT3A1 isoform, is essential for these interactions and stabilises H3K36me2-nucleosome recruitment. Intriguingly, in the same region critical for nucleosome binding we also map a ubiquitylation-dependent recruitment motif (UDR). The UDR binds specifically to ubiquitylated H2AK119, explaining the previously observed recruitment to Polycomb-occupied heterochromatin. A cryo-EM structure of DNMT3A1-DNMT3L with a modified nucleosome reveals that the UDR interacts with the nucleosome surface including the acidic patch. Previously unexplained disease-associated mutations are present in the UDR and ablate nucleosome interactions. This leads to an increased understanding of how DNMT3A1 recruitment occurs in the genome and highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome.

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Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Bulk RNA-Seq)

Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human acute myeloid leukemia (AML) cases with a 5-year overall survival of approximately 30%. In CN-AML with poorer prognosis, mutations in the de novo DNA methyltransferase (DNMT3A) and the FMS-like tyrosine kinase 3 (Flt3) commonly co-occur (1-3). We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. These murine AML retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML demonstrate a similar pattern of global DNA methylation. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Differentially methylated genomic regions were associated with changes in the expression of nearby genes. Moreover, dissection of the cellular architecture of the AML model using single-cell RNA-Seq, flow cytometry and colony assays identified clonogenic subpopulations that differentially express genes that are sensitive to the methylation of nearby genomic loci and varied in response to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. To identify the gene expression changes associated with Dnmt3a loss of function in human and murine Flt3-ITD and Dnmt3a-mutant AML (Bulk RNA-Seq).

2016-03-27 | E-GEOD-77846 | biostudies-arrayexpress

Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Single Cell RNA-Seq)

2016-03-27 | E-GEOD-77847 | biostudies-arrayexpress

Mouse lung tumor tissue: Dnmt3a KO vs. Dnmt3a WT

2011-10-26 | GSE32415 | GEO

DNMT3A and TET2 Mutations Increase Hematopoietic Stem Cell Fitness Through Distinct Mechanisms

Project description:Epigenetic modifying enzymes DNMT3A and TET2 are recurrently mutated in hematological disorders despite possessing opposing biochemical functions in the DNA methylation processes. Using conditional ablation, we show these contrasting genotypes result in different functional effects in hematopoietic stem cells (HSCs). Loss of Dnmt3a bestows enhanced self-renewal on HSCs in serial, competitive repopulation assays while Tet2 loss functionally depletes HSCs after a tertiary transplant despite an initial competitive advantage. Moreover, loss of Tet2 sensitizes HSCs to the addition of a common leukemic driver mutation Flt3-ITD. Tet2-null mice experience a 5-fold decrease in median survival time when combined with Flt3-ITD while that of Dnmt3a-null mice decreases 1.5-fold. Molecular characterization of transcriptomes and chromatin accessibility reflects the functional differences between the genotypes as Dnmt3a-null cells reside in a more stem cell-like state while Tet2 loss leads to functional attrition of down-stream progenitors. These data further prove that DNMT3A and TET2 mutations lead HSCs down different molecular and functional pathways despite similar disease destinations.

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