Project description:Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBP?), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

| S-EPMC6330064 | biostudies-literature

Subtype-specific regulatory network rewiring in acute myeloid leukemia [Hi-C]

Project description:Acute myeloid leukemia is a heterogeneous disease which is subdivided into different categories defined by disease-causing mutations in transcription factors, epigenetic regulators and signalling molecules. How different mutant regulators establish AML-specific transcriptional networks is unclear. Here we performed a comprehensive analysis of mutation-specific sets of cis-regulatory elements driving gene expression in AML blast cells from a carefully selected group of patients with alterations in genes encoding transcription factors (RUNX1, CEBPA) and signalling molecules (FTL3-ITD, RAS, NPM1). We show that each mutant regulator establishes a specific transcriptional and signalling network unrelated to normal cells driving the expression of unique sets of genes required for AML survival.

2018-09-20 | GSE108303 | GEO

Subtype-specific regulatory network rewiring in acute myeloid leukemia [RNA-seq]

2018-09-20 | GSE108266 | GEO

Subtype-specific regulatory network rewiring in acute myeloid leukemia [DNase-Hypersensitivity]

2018-09-20 | GSE108246 | GEO

Subtype-specific regulatory network rewiring in acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-09-20 | GSE108316 | GEO

Rewiring of the Transcription Factor Network in Acute Myeloid Leukemia.

Project description:Acute myeloid leukemia (AML) is a highly heterogeneous cancer associated with different patterns of gene expression determined by the nature of their DNA mutations. These mutations mostly act to deregulate gene expression by various mechanisms at the level of the nucleus. By performing genome-wide epigenetic profiling of cis-regulatory elements, we found that AML encompasses different mutation-specific subclasses associated with the rewiring of the gene regulatory networks that drive differentiation into different directions away from normal myeloid development. By integrating epigenetic profiles with gene expression and chromatin conformation data, we defined pathways within gene regulation networks that were differentially rewired within each mutation-specific subclass of AML. This analysis revealed 2 major classes of AML: one class defined by mutations in signaling molecules that activate AP-1 via the mitogen-activated protein (MAP) kinase pathway and a second class defined by mutations within genes encoding transcription factors such as RUNX1/CBFβ and C/EBPα. By identifying specific DNA motifs protected from DNase I digestion at cis-regulatory elements, we were able to infer candidate transcription factors bound to these motifs. These integrated analyses allowed the identification of AML subtype-specific core regulatory networks that are required for AML development and maintenance, which could now be targeted in personalized therapies.

| S-EPMC6595639 | biostudies-literature

Transcription profiling of human hematopoietic stem cell like fractions from individuals with the M2 subtype of acute myeloid leukemia

Project description:AC133+ cells were prepared from bone marrow of individuals with acute myeloid leukemia (AML) with M2 subtype. Comparison was made between de novo AML and MDS-associated AML.

2003-10-09 | E-MEXP-25 | biostudies-arrayexpress

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