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Title: Dnmt3a haploinsufficiency transforms Flt3-ITD myeloproliferative disease into a rapid, spontaneous, and fully-penetrant acute myeloid leukemia (Bulk RNA-Seq)      
keywords:
Transcriptome or Gene expression
ID:
PRJNA311724
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. Overall design: 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).
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA311724
authentication:
none
authorization:
none
ID:
pmid:27016502
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 CA159845/CA/NCI NIH HHS/United States

  • T32 ES007250/ES/NIEHS NIH HHS/United States

  • U01 HL099997/HL/NHLBI NIH HHS/United States

  • U24 CA196172/CA/NCI NIH HHS/United States

  • R21 CA186945/CA/NCI NIH HHS/United States

  • P30 CA008748/CA/NCI NIH HHS/United States

  • UL1 TR001425/TR/NCATS NIH HHS/United States

  • U10 CA180820/CA/NCI NIH HHS/United States

  • T32 GM008752/GM/NIGMS NIH HHS/United States

  • R01 CA196658/CA/NCI NIH HHS/United States

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