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Intrinsic Protection From Leukemic Transformation at The Level of Hematopoietic Stem Cells

ABSTRACT: Genome wide RNA-seq from pGM and HSCs in response to expression of the MLL-ENL fusion gene Examination of mRNA abundance in two cell types with or without induction of the MLL-ENL fusion gene (following 48h of culture)

ORGANISM(S): Mus musculus

SUBMITTER: Shamit Soneji

PROVIDER: E-GEOD-62734 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.

Ugale Amol A Norddahl Gudmundur L GL Wahlestedt Martin M Säwén Petter P Jaako Pekka P Pronk Cornelis Jan CJ Soneji Shamit S Cammenga Jörg J Bryder David D

Cell reports 20141113 4

Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can o ...[more]

PMID: 25456127

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Intrinsic Protection From Leukemic Transformation at The Level of Hematopoietic Stem Cells

Project description:Genome wide RNA-seq from pGM and HSCs in response to expression of the MLL-ENL fusion gene

2015-01-01 | GSE62734 | GEO

Protein Interactions of 7 MLL-fusion Proteins

Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.

2018-05-25 | PXD009338 | Pride

Genome-wide analysis of gene expression in MLL translocation transformed mouse leukemia cell lines

Project description:The purpose of this study is to investigate the transcriptional programs as it relates to disease latency initiated by different MLL fusion proteins, including: MLL-AF1p, MLL-AF6, MLL-Gas7, MLL-AF9 and MLL-ENL. Leukemia cell lines were established by transforming kit+ mouse bone marrow cells with retroviruses coding MLL-AF1p, MLL-AF6, MLL-Gas7, MLL-AF9 or MLL-ENL. At early phase after the cell lines were established, cells growing at exponential phase (cell density at 0.5~1x106/ml) were harvested for RNA extraction and sequencing purpose. Sequencing is performed on total RNA isolated from mouse leukemia cell lines generated from kit+ mouse bone marrow cells transduced with various MLL fusion proteins and is compared to control total RNA isolated from kit+ mouse bone marrow cells.

2016-07-07 | E-GEOD-73457 | biostudies-arrayexpress

MLL Fusion Proteins Preferentially Regulate a Small Set of Wild Type MLL Target Genes in the Leukemic Genome

Project description:MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations encode chimeric MLL fusions that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of the MLL fusion protein. By comparing patient-derived leukemic cell lines, we find that MLL fusion-bound genes are a small subset of that recognized by wild-type MLL. In an inducible MLL-ENL cellular model, binding of the MLL fusion protein and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL fusion-bound genes, only 12 demonstrate a significant increase in mRNA expression upon induction of the fusion protein. In addition to Hoxa9 and Meis1, this includes Eya1 and Six1 which comprise a heterodimeric transcription factor important in several developmental pathways. We show that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, our data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes. We explored an inducible MLL-ENL cellular model, which was obtained from Dr. Robert Slany (University Erlangen, Germany). We wished to examine the differential expressed genes that are bound by MLL wild type (No 4-OHT) and fusion (4-OHT) proteins, combinding the ChIP-chip data to explore the potential MLL fusion-regulated genes.

2011-04-28 | E-GEOD-24794 | biostudies-arrayexpress

Expression data from conditionally immortalized MLL-AF9 and MLL-ENL hematopoietic progenitor cells following loss of MLL-fusion oncogene

Project description:Chromosomal translocations encoding the MLL-AF9 and MLL-ENL fusion transcription factors are prevalent in infant acute leukaemia and therapy-related leukaemia. In order to conditionally express the MLL-fusion oncogene in primary haematopoietic progenitor cells (HPC), retroviral delivery of the Tet-off expression system was used (Horton et al., Cancer Res, 2005). Treatment of the conditional cells with Doxycycline caused a decrease in MLL-AF9/ENL mRNA and protein expression, and resulted in terminal differentiation of the cells. By analysing global changes in gene expression after treatment of cells with Doxycycline we were able to identify a number of potential transcriptional target genes of the MLL-AF9 and MLL-ENL fusion oncogenes.

2014-12-01 | GSE59236 | GEO

Runx1 deficiency effect on MLL-ENL cells

Project description:To identify the target genes of Runx1 in MLL fusion leukemia, we performed microarray analysis using control and Runx1-deficient MLL-ENL leukemia cells. Runx1 intact and excised bone marrow cells were transduced with MLL-ENL and transplanted into congenic mice. Leukemic cells were harvested from moribund mice, and gene expression was compared using 3 independent leukemia cells for each genotype.

2013-06-30 | E-GEOD-47402 | biostudies-arrayexpress

Development of MLL-rearranged leukemia is dependent on a transcriptional program orchestradt by C/EBPα

Project description:Translocations involving the MLL genes are frequently found in Acute Myeloid Leukemia (AML) and are associated with poor prognosis. The MLL fusion proteins act as aberrant transcription factor activating a transcriptional program that transforms the cells, potentially through collaboration with other transcription factors. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPα to be up-regulated in the AML samples, suggesting that C/EBPα might collaborate with MLL fusion proteins in the initial transformation process. We could show that transformation by MLL fusion proteins is dependent on C/EBPα activity both in early progenitors as well as in GMPs. In contrast, C/EBPα was found to be indispensable in an already established leukemia. These results suggest that C/EBPα play an important role in the early transforming event of leukemogenesis. We used microarray to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPα / MLL-ENL transcriptional signature. 3 Cebpaflox/flox;Mx1Cre and 3 Cebpaflox/flox;Mx1Cre- mice were sacrificed 14 days after pIpC injection and bone marrow cells were harvested, enriched for cKit-expression and transduced with a pMIG retroviral vector expressing the MLL-ENL fusion protein and GFP. 72 h post first transduction, GFP-positive or negative PreGM cells were sorted.

2013-12-10 | E-GEOD-46534 | biostudies-arrayexpress

Runx1 deficiency effect on MLL-ENL cells

Project description:To identify the target genes of Runx1 in MLL fusion leukemia, we performed microarray analysis using control and Runx1-deficient MLL-ENL leukemia cells.

2013-06-30 | GSE47402 | GEO

Genome-wide analysis of gene expression in MLL translocation transformed mouse leukemia cell lines

2016-07-07 | GSE73457 | GEO

Quantitative cellular proteome analysis of Fetal- and Adult-Derived MLL-Rearranged Leukemia

Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.

2024-04-02 | PXD042249 | Pride

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