Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression and ChIP-chip data from REH and SEM leukemia cell lines

ABSTRACT: MLL-fusion proteins are potent inducers of cancer in hematopoietic cells, where they are known to cause changes in global gene expression. How MLL-fusion proteins interact with the genome has not been established, so we have limited understanding of the pathway by which these proteins generate aberrant gene expression programs. Here we describe how the MLL-AF4 protein occupies the genome in human leukemia cells and its striking effects on chromatin states. We find that the MLL-AF4 fusion protein selectively occupies regions of the genome that contain developmental regulatory genes important for hematopoietic stem cell identity and self-renewal. These MLL-AF4 bound regions have grossly altered chromatin structure, with histone modifications catalyzed by Trithorax Group (TrxG) proteins and Dot1 extending across unusually large domains. This indicates that a key feature of MLL-associated leukemogenesis is aberrant targeting of chromatin modifiers to regions of the genome controlling hematopoietic development. Our results define the direct targets of the MLL-fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in human cancer. Keywords: cell type comparison This dataset includes expression data for two replicates each of SEM and REH leukemia cell lines and ChIP-chip data targeting RNAP2, H3K4me3, H3K79me2, ENL, AF4-C, and MLL-N in SEM and REH leukemia cell lines.

ORGANISM(S): Homo sapiens

SUBMITTER: Garrett Frampton

PROVIDER: E-GEOD-13313 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia.

Guenther Matthew G MG Lawton Lee N LN Rozovskaia Tatiana T Frampton Garrett M GM Levine Stuart S SS Volkert Thomas L TL Croce Carlo M CM Nakamura Tatsuya T Canaani Eli E Young Richard A RA

Genes & development 20081201 24

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across ...[more]

PMID: 19141473

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Project description:The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well-established that MLL-AF4 arises pre-natally during human development, its effects on hematopoietic development in utero remains unexplored. We have created a human-specific in vitro system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Differentiation and functional studies as well as clonal analyses and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. It enhances the specification of hemogenic precursors from hESCs and impairs further hematopoietic commitment of these precursors in favour of the endothelial cell fate. Similar to that reported in cord blood CD34+ hematopoietic stem/progenitor cells (HSPCs), MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells in vitro or in vivo, indicating that additional events may be required to initiate leukemogenesis or that embryonic hematopoiesis is not the appropriate human cellular target for MLL-AF4-mediated leukemogenesis. This work illustrates how hESCs can provide unique insights into human development and further our understanding of how leukemic fusion genes known to arise pre-natally regulate human embryonic hematopoietic specification. MLL is involved in transcriptional regulation and most MLL translocations appear to result in increased expression of Hox genes and hematopoietic genes. We therefore assessed the impact of MLL-AF4 expression on the transcriptome of hESCs. Gene expression profiling performed in MLL-AF4 hESCs revealed that MLL-AF4 preferentially activates transcription. 1826 out of the 3001 genes (61%) expressed were up-regulated in MLL-AF4 hESCs. Human ESC samples were collected during the exponential cell growth phase and stabilized in RNA later. 500 ng of each total RNA sample was labelled with Cy3 using the Quick-Amp Labelling kit and hybridized with the Gene Expression Hybridization kit to a Whole Human Genome Oligo Microarray (Agilent Technologies) following the Manufacturer’s instructions. Each cell line was analyzed as independent duplicates. NEO-expressing (empty lentivector) hESC line was used as the baseline.

Project description:Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. We performed DNA methylation (HELP array) and gene expression profiling in 215 samples of adult B-lineage acute lymphoblastic leukemia (ALL) and 12 normal preB samples. Adult B-lineage acute lymphoblastic leukemia (B-ALL) is an aggressive disease with <40% long-term survival. Genetic alterations such as BCR/ABL, E2A/PBX1 and MLL rearrangement (tMLL) define distinct B-ALL subtypes, which are associated with poor clinical outcome. It has been shown that these B-ALL subtypes have distinct expression profiles. However, the role of the epigenome in shaping these expression profiles and how the aberrant epigenetic gene regulation contributes to the biological and clinical features of those ALL subtypes is largely unknown. To address this question, we performed genome-wide DNA methylation and gene expression profiling on a large cohort of 215 well-characterized adult B-ALL specimens from the ECOG E2993 phase III clinical trial and a cohort of normal precursor B (preB) cells from 12 healthy bone marrows. The integrative analysis of these profiles led to the identification of key gene networks deregulated at the epigenetic and transcriptional levels within each subtype. In BCR/ABL, we identified a network centered on IL2RA(CD25), which is itself hypomethylated and overexpressed in most BCR/ABL B-ALL and confers poor clinical outcomes. In the tMLL subtype, we uncovered aberrant epigenetic and transcriptional activities that include hypomethylation and upregulation of FLT3 and BCL6. After showing that MLL/AF4 fusion protein binds to these genes as well as other hypomethylated and overexpressed genes in tMLL ALL cells, we showed that a specific BCL6 inhibitor, RI-BPI, kills tumor cells in both tMLL ALL cell lines and patient samples. BCL6 inhibition may therefore represent a novel therapeutic strategy for B-ALL patients with MLL translocations. RUNX1 is a key target gene in MLL-AF4 leukemias and contributes to gene activation by interacting with the AF4-MLL complex. The Mixed Lineage Leukemia 1 protein (MLL1) is an important epigenetic protein that is required for the maintenance of gene activation during development, but is also mutated in a subset of aggressive human leukemias. The most common leukemogenic MLL1 mutations are chromosome translocations that fuse MLL1 in-frame to produce novel fusion proteins. Different MLL1 fusion proteins cause unique leukemias even when they are expressed in the same cell type, suggesting that they function through unique molecular mechanisms. We used ChIP-seq in MLL-AF4 patient cell lines to identify target genes that are involved in leukemogenesis. ChIP-seq using MLLN, AF4, H3K4me3 and H3K79me2 antibodies in RS4;11 cells.

Dataset Information

Expression and ChIP-chip data from REH and SEM leukemia cell lines

Publications

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia.

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