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Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition

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

ORGANISM(S): Homo sapiens

SUBMITTER: Sara Alvarez

PROVIDER: E-GEOD-54348 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition (microarray)

Project description:We investigated the response of acute myeloid cells (AML) expressing MLL-AF9 fusion gene to the pan-HDACi panobinostat (LBH589), and found that low conentrations of panobinostat lead to MLL-AF9 cell toxicity and rapid changes in gene expression. Human hematopoietic stem/progenitor cells (HSPC) expressing MLL-AF9 fusion protein (Wei et al, Cancer Cell 2008) were cultured with 30 nM panobinostat during 6 and 24 hours. The different gene expression between cells treated and untreated was studied by gene expression analysis. Three independent HSPC-MA9 clones were used, for each two replicates of cells after culture with 30 nM panobinostat for 6 and 24 hours and one untreated were used. A total of 16 samples were analyzed.

2015-03-01 | E-GEOD-54218 | biostudies-arrayexpress

Aberrant chromatin acetylation in MLL-AF9 leukemia mediates the response to HDAC inhibition (ChIP-Seq)

Project description:We studied the chromatin modification patterns induced by the presence of the MLL-AF9 fusion protein in a model of human hematopoietic stem/progenitor cells (HSPC) transduced with retrovirus expressing MLL-AF9cDNA (HSPC-MA9). Comparative ChIP-seq analysis between HSPC-MA9 and control HSPC, revealed a massive hyperacetylation of histones that was consistent with the transcriptional profile in the presence of MLL-AF9 fusion protein. Furthermore, we identified 66 MLL-AF9 targets, and found that H4ac was present along with H3K4me3 and H3K79me2 chromatin marks in over 50% of the MLL-AF9 target genes. Examination of histone aceylation and methylation changes upon expression of MLL-AF9 fusion protein in human hematopoietic stem/progenitor cells.

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Integrative epigenomic analysis in MLL-AF9 acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL)

Project description:Next generation DNA sequencing of acute myeloid leukemia (AML) patient samples has revealed novel recurrent mutations while at the same time highlighting the genetic heterogeneity of the disease. These observations suggest that an extraordinarily large number of combinations of mutations can contribute to leukemogenesis. In order to address the question of the contribution of patient genetic background to AML we have developed a model system to generate multiple human leukemias in a single donorâs genetic background. Stepwise RNA-seq data from this model shows that in the context of AML driven by the MLL-AF9 (MA9) oncogene, the genetic background of the donor does not have a detectable effect. Comparison of these model leukemias from multiple single donors to AML patient samples containing MA9 translocations revealed conserved gene expression patterns not previously highlighted in this genetic sub-type. We further demonstrate that the expression of one of these genes, RET, is essential both in vivo and in vitro growth of MA9 AMLs . study of methylome during the development of MLL-AF9 AML

2017-05-02 | E-GEOD-70755 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (array)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of gene expression dynamics with and without drug treatment and RNA interference.

2015-03-30 | E-GEOD-61013 | biostudies-arrayexpress

Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

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

2016-06-29 | E-GEOD-68463 | biostudies-arrayexpress

Integrated analysis of MLL-AF9 AML patients and model leukemias highlights RET and other novel therapeutic targets

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

2015-08-04 | E-GEOD-71691 | biostudies-arrayexpress

Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary

Project description:To identify such targets of leukemia-related miRNAs such as miR-196b, we conducted Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) recipient mice A total of 24 mouse bone marrow samples including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) obtained from the in vivo mouse bone marrow reconstitution assays were analyzed by use of Affymetrix GeneChip Mouse Gene 1.0 ST Array (Affymetirx, Santa Clara, CA)

2012-08-09 | E-GEOD-34185 | biostudies-arrayexpress

RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by tet-regulated MLL-AF9 co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in Tet-Off MLL-AF9 AML cells in vitro partially phenocopies MLL-AF9 depletion and results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. To compare gene expression changes associated with enforced Id2 expression and MLL-AF9 withdrawal, RNA sequencing analysis was performed on Tet-off MLL-AF9 cells transduced with an Id2 over-expressing or a control vector, or upon MLL-AF9 dox-inducible knock-down. Primary AMLs driven by Tet-off inducible MLL/AF9 expression linked to dsRED reporter, in association with oncogenic NRASG12D (Tet-off MLL-AF9) were generated by reconstituting lethally irradiated congenic mice with foetal liver cells co-transduced with a Tet-Off-MLL-AF9-dRED retroviral vector and a second vector co-expressing NRASG12D together with the Tet-Off responsive transcriptional activator. RNA sequencing analysis sequencing analysis was performed on Tet-Off MLL-AF9/dsRED+ AML cells treated in vitro with doxycycline (DOX) for 4 days to inactivate MLL-AF9 expression or left untreated (UT). For the Id2 over-expression experiment, Tet-Off MLL-AF9/dsRED+ AML cells were transduced in vitro with an Id2-GFP or a control-GFP retroviral vector. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis.

2016-06-29 | E-GEOD-68462 | biostudies-arrayexpress

Epigenetic profiling of hematopoietic stem cells and leukemia stem cells

Project description:The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations that involve the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in a murine MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3 and H3K36me3. Histone methylation patterns are highly abnormal on MLL-AF9 fusion target loci, defining a distinct epigenetic lesion involving H3K79. Conditional inactivation of Dot1l leads to specific down-regulation of direct MLL-AF9 targets and an MLL-translocation associated gene expression signature, while global transcription levels remain largely unaffected. This correlated with a greater sensitivity of leukemic blasts towards loss of Dot1l compared to normal hematopoietic cells. Development of in vivo leukemia was absolutely dependent on Dot1l. Chromatin immunoprecipitation followed by Solexa sequencing for H3K4me3, H3K27me3, H3K36me3, H3K79me2 and biotinylated MLL-AF9 in HSC, GMP and LSC.

2011-09-13 | E-GEOD-29130 | biostudies-arrayexpress

miR-196b targets both oncogenic and tumor suppressor genes in MLL-associated leukemia

Project description:This SuperSeries is composed of the following subset Series: GSE34184: Affymetrix Human Exon 1.0 ST array assay of 15 human MLL-associated samples and 9 human normal bone marrow [HuEx-1_0-st] GSE34185: Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary Refer to individual Series

2012-08-12 | E-GEOD-34186 | biostudies-arrayexpress

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