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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54348 | GEO | 2015/03/01

SECONDARY ACCESSION(S): PRJNA236240

REPOSITORIES: GEO

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

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

2015-03-01 | E-GEOD-54348 | biostudies-arrayexpress

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.

2015-03-01 | E-GEOD-54344 | biostudies-arrayexpress

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

2015-03-01 | GSE54218 | GEO

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

2015-03-01 | GSE54344 | GEO

Human MLL-AF9 Overexpression Induces Aberrant Hematopoietic Expansion in Zebrafish.

Project description:The 11q23 of the mixed lineage leukemia 1 (MLL1) gene plays a crucial role in early embryonic development and hematopoiesis. The MLL-AF9 fusion gene, resulting from chromosomal translocation, often leads to acute myeloid leukemia with poor prognosis. Here, we generated a zebrafish model expressing the human MLL-AF9 fusion gene. Microinjection of human MLL-AF9 mRNA into zebrafish embryos resulted in enhanced hematopoiesis and the activation of downstream genes such as meis1 and hox cluster genes. Embryonic MLL-AF9 expression upregulated HSPC and myeloid lineage markers. Doxorubicin and MI-2 (a menin inhibitor) treatments significantly restored normal hematopoiesis in MLL-AF9-expressing animals. This study provides insight into the role of MLL-AF9 in zebrafish hematopoiesis and establishes a robust and efficient in vivo model for high-throughput drug screening.

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Meis1 maintains stemness signature in MLL-AF9 leukemia.

Project description: Not available

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Corrigendum to "Human MLL-AF9 Overexpression Induces Aberrant Hematopoietic Expansion in Zebrafish".

Project description:[This corrects the article DOI: 10.1155/2018/6705842.].

| S-EPMC8800627 | biostudies-literature

Polycomb repressive complex 2 is required for MLL-AF9 leukemia.

Project description:A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML.

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Reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells.

Project description:The 'Yamanaka factors' (Oct4, Sox2, Klf4 and c-Myc) are able to generate induced pluripotent stem (iPS) cells from different cell types. However, to what degree primary malignant cells can be reprogrammed into a pluripotent state has not been vigorously assessed. We established an acute myeloid leukemia (AML) model by overexpressing the human mixed-lineage leukemia-AF9 (MLL-AF9) fusion gene in mouse hematopoietic cells that carry Yamanaka factors under the control of doxycycline (Dox). On addition of Dox to the culture, the transplantable leukemia cells were efficiently converted into iPS cells that could form teratomas and produce chimeras. Interestingly, most chimeric mice spontaneously developed the same type of AML. Moreover, both iPS reprogramming and leukemia reinitiation paths could descend from the same leukemia-initiating cell. RNA-seq analysis showed reversible global gene expression patterns between these interchangeable leukemia and iPS cells on activation or reactivation of MLL-AF9, suggesting a sufficient epigenetic force in driving the leukemogenic process. This study represents an important step for further defining the potential interplay between oncogenic molecules and reprogramming factors during MLL leukemogenesis. More importantly, our reprogramming approach may be expanded to characterize a range of hematopoietic malignancies in order to develop new strategies for clinical diagnosis and treatment.

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