Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Sara Alvarez

PROVIDER: E-GEOD-54344 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MLL-AF9 expression in normal human umbilical cord blood CD34+ cells leads to long-term proliferation of a myeloid progenitor cell with leukemogenic potential. Expression of a Core Binding Factor leukemia fusion (AML1-ETO or CBFbeta-SMMHC) in human CD34+ cells results in self-renewal of primitive progenitor cells with multilineage potential and stem cell ability, but these cells do not induce leukemia in immunodeficient mice. This comparative microarray study was initiated to determine how faithful these cell cultures are to the transcriptome of patient samples expressing each of these different fusion proteins, and to analyze the signaling pathways that are unique to CBF cultures and MLL-fusion cultures, with the hope of determining why the MLL-fusion cells are leukemogenic while the CBF cells are not. Experiment Overall Design: We have established a culture system whereby we retrovirally transduce human CD34+ cells, obtained from cord blood, with the leukemia fusion genes MLL-AF9 (MA9), AML1-ETO (AE) or CBFbetaMYH11 (CM). Cells expressing each of these fusion proteins are able to proliferate long-term in vitro in a cytokine dependent manner. These cultures resemble somewhat the blast samples from patients that contain these different fusion proteins, in that MA9 cells are predominantly monocytic (M5-like), AE cells have a large population of primitive CD34+ cells with continued abnormal differentiation (M2-like) and CM cells also contain a population of primitive CD34+ cells with continued abnormal differentiation but also have a significant population of abnormal eosinophils (M4Eo). We grow these cells in the presence of fetal bovine serum (FBS), and also grow them in serum-free conditions using the BIT supplement from Stem Cell Technologies. For the current experiments we used cell cultures that had been proliferating in vitro for 8-12 weeks, in either serum-free conditions or with FBS. Replicate samples were included in some instances, and the same clonal cultures that were grown under either BIT or FBS were also included.

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

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