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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (expression)

ABSTRACT: Here, we analyzed global gene expression changes that were associated with over expression of Dnmt3b in MLL-AF9 induced leukemias using the Affymetrix microarray platform.

ORGANISM(S): Mus musculus

PROVIDER: GSE71040 | GEO | 2016/01/11

SECONDARY ACCESSION(S): PRJNA290165

REPOSITORIES: GEO

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (expression)

Project description:Here, we analyzed global gene expression changes that were associated with over expression of Dnmt3b in MLL-AF9 induced leukemias using the Affymetrix microarray platform. Changes in global gene expression were determined with Affymetrix microarrays in MLL-AF9 induced leukemias over expressing Dnmt3b.

2016-01-11 | E-GEOD-71040 | biostudies-arrayexpress

Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (RRBS)

Project description:The de novo DNA methyltransferases Dnmt3a and Dnmt3b are of crucial importance in hematopoietic stem cells, and Dnmt3b has recently been shown to play a role in genic methylation. Forced Dnmt3b expression induced widespread DNA hypermethylation in myc-bcl2 induced leukemias, especially at promoters and gene bodies of stem cell-related genes. MLL-AF9 induced leukemogenesis showed much less pronounced DNA hypermethylation upon Dnmt3b expression. Nonetheless, leukemogenesis was delayed in both models with a shared core set of DNA hypermethylated regions and suppression of stem cell-related genes. Our findings indicate a critical role for Dnmt3b-mediated DNA methylation in leukemia development and maintenance of LSC function. To investigate how Dnmt3b-mediated DNA methylation affects leukemogenesis, we analyzed leukemia development under conditions of high and physiological methylation levels in a tetracycline-inducible knockin mouse model. High expression of Dnmt3b slowed leukemia development in serial transplantations and impaired leukemia stem cell (LSC) function.

2016-01-11 | E-GEOD-71039 | biostudies-arrayexpress

Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (RRBS)

2016-01-11 | GSE71039 | GEO

Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-11 | E-GEOD-71041 | biostudies-arrayexpress

Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-01-11 | GSE71041 | GEO

Gene expression profiling of the MLL-AF9 induced AML cells (wild type and Dnmt3b-KO)

Project description:Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder with a poor prognosis. Abnormal DNA methylation is involved in the initiation and development of AML. The de novo methyltransferases Dnmt3a and Dnmt3b are responsible for the generation of genomic methylation patterns. While DNMT3A is frequently mutated in hematologic malignancies, DNMT3B is rarely mutated. To investigate the role of Dnmt3b in AML, we genetically inactivated Dnmt3b in an MLL-AF9 induced AML mouse model. Gene profiling using a microarray revealed the upregulation of the oncogenic gene set and the downregulation of the cell differentiation gene set. Our results indicate that Dnmt3b plays the role of a tumor suppressor in MLL-AF9 AML progression, which reveals new insights into the roles of DNA methylation in leukemic development.

2016-07-01 | GSE75401 | GEO

Histone H3K36me2-specific methyltransferase ASH1L promotes the MLL-AF9-induced leukemogenesis

Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.

2021-09-07 | GSE183413 | GEO

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

2015-04-30 | GSE64365 | GEO

Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Project description:The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemias are consistently poor prognosis. One of the most common translocation partners is AF9 (a.k.a. MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites, and present the NMR solution structure of a DOT1L-AF9 complex. We generated structure-guided point mutations with graded effects on recruitment of DOT1L to MLL-AF9. ChIP-Seq analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in selective losses in H3K79me2 and me3 marks at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment defines the level of MLL-AF9 hematopoietic transformation. Hematopoietic progenitor cells isolated from mouse bone marrow were transduced with retrovirus expressing either wildtype MLL-AF9 (WT), mutants, MLL-AF9 (D544R) and MLL-AF9 (D546R). ChIP-Seq analyses were performed on these wildtype and mutant cells using H3K79me2 and H3K79me3 antibodies. 3 samples corresponding to ChIP-Seq with H3K79me2 antibody: 1) MLL-AF9 (WT) 2) MLL-AF9 (D544R) 3) MLL-AF9 (D546R) 3 Samples Corresponding to ChIP-Seq with H3K79me3 antibody: 4) MLL-AF9 (WT) 5) MLL-AF9 (D544R) 6) MLL-AF9 (D546R)

2015-04-30 | E-GEOD-64365 | biostudies-arrayexpress

Gene expression induced by DOT1L and Menin inhibition in cell line models of leukemia

Project description:Gene expression upon DOT1L inhibition, or Menin inhibition, or a combination of DOT1L and Menin inhibiting agents, was assessed in several MLL-rearranged human cell lines and a mouse model of MLL-AF9 leukemia. The goal of the study was to explore the mechanisms by which the EPZ0004777 and MI-2-2 chemicals collaborate to induce differentiation and cell death in MLL-AF4 and MLL-AF9 leukemias.

2016-11-14 | GSE63664 | GEO

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