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Genome-wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

ABSTRACT: Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation which were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE25539 | GEO | 2011/02/17

SECONDARY ACCESSION(S): PRJNA134013

REPOSITORIES: GEO

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Genome-wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

Project description:Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation which were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer. To monitor global expression changes during leukaemia progression for both MLL-ENL and MOZ-TIF1, we performed gene expression profiling for three biological replicates each of the lin-/kit+ bone marrow (WT), Factor-Dependent Cells Patterson-Mix cells (FDCP), MLL-ENL initiation (ME-I), MOZ-TIF2 initiation (MT-I), MLL-ENL progression (ME-L) and MOZ-TIF2 progression (MT-L) samples. Biotin-labelled cRNA from three biological replicates was generated from 250ng of total RNA and hybridized onto MouseWG-6 version 2 Expression Bead Chips.

2011-02-17 | E-GEOD-25539 | biostudies-arrayexpress

Effect of Ythdf2 in haematopoiesis [RNA-seq]

Project description:The mRNA m6A reader YTHDF2 is overexpressed in human acute myeloid leukaemias. To understand the role of YTHDF2 in normal haematopoiesis and ageing, we performed SMART-seq on haematopoietic stem cells (HSCs) derived from young and aged (1 year old) mice. In parallel, to identify transcripts likely methylated in HSCs we performed meRIP-seq analysis of c-Kit+ cells.

2020-10-29 | GSE142019 | GEO

Effect of Ythdf2 in haematopoiesis [meRIP-seq]

2020-10-29 | GSE142020 | GEO

Identification of drugs in leukaemia differentiation therapy by network pharmacology

Project description:Acute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant transcriptional reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm for predicting reprogramming factors, to identify TFs and their gene regulatory networks that drive ATRA-induced differentiation of the acute promyelocytic leukaemia (APL) cell line NB4. We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule compounds which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide a proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

2022-11-08 | GSE131325 | GEO

Effect of Cited2 knockout on gene expression in haematopoietic stem cells

Project description:The pleiotropic transcriptional regulator CITED2 is essential for lifelong maintenance of haematopoiesis. To understand the molecular roles of CITED2 in normal haematopoiesis, we performed RNA-sequencing on CD48−CD150+ haematopoietic stem cells (HSCs) derived from young mice.

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Transcription profiling of human paediatric acute lymphoblastic leukaemia

Project description:We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionising radiation (IR)-induced DNA double strand breaks in 74 paediatric ALL patients. We found an apoptosis-resistant response in 36% of patients and an apoptosis-sensitive response in the remaining 64% of leukaemias. Global gene expression profiling of 11 apoptosis-resistant and 11 apoptosis-sensitive ALLs revealed abnormal up-regulation of multiple pro-survival pathways in response to IR in apoptosis-resistant leukaemias and differential post-transcriptional activation of the PI3-Akt pathway was observed in representative resistant cases. It is possible that abnormal pro-survival responses to DNA damage provide one of the mechanisms of primary resistance in ALL . Experiment Overall Design: Twenty two B-precursor ALL tumours (11 responsive to IR-induced DNA damage and 11 resistant) were analysed before and 8 hours after exposure to 5 Gy IR, using the Affymetrix HG_U133A (GPL96) platform.

2008-11-13 | E-GEOD-13280 | biostudies-arrayexpress

Gene expression analysis of paediatric acute lymphoblastic leukaemia

Project description:We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionising radiation (IR)-induced DNA double strand breaks in 74 paediatric ALL patients. We found an apoptosis-resistant response in 36% of patients and an apoptosis-sensitive response in the remaining 64% of leukaemias. Global gene expression profiling of 11 apoptosis-resistant and 11 apoptosis-sensitive ALLs revealed abnormal up-regulation of multiple pro-survival pathways in response to IR in apoptosis-resistant leukaemias and differential post-transcriptional activation of the PI3-Akt pathway was observed in representative resistant cases. It is possible that abnormal pro-survival responses to DNA damage provide one of the mechanisms of primary resistance in ALL . Keywords: Gene expression profiling; response to irradiation

2008-10-23 | GSE13280 | GEO

Haemopedia: An Expression Atlas of Murine Haematopoietic Cells

Project description:Haematopoiesis is a multi-stage process that involves the differentiation of multipotent stem cells and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, a comprehensive atlas of murine gene expression data that covers all the mature lineages in haematopoiesis, including rare cell populations such as eosinophils, mast cells, basophils and megakaryocytes and a large collection of progenitor and stem cells. We have used this dataset to identify gene sets with specifically enriched expression in each of the mature blood cell lineages. Many of the genes in these sets show conserved lineage-enriched expression patterns in human haematopoiesis. We also identify some genes with divergent expression patterns between mouse and human, highlighting species specific differences in blood cell production. To make analyses of Haemopedia and other blood cell transcriptional datasets easier, we have created an online web portal, Haemosphere, which provides simple tools to interrogate gene expression-based relationships between haematopoietic cell types and genes of interest. Total RNA was obtained from 54 haematopoetic cells types and 8 non-haematopoietic out groups.

2016-07-17 | E-GEOD-77098 | biostudies-arrayexpress

Functional and genetic heterogeneity of distinctive leukaemic stem cell populations in CD34- human Acute Myeloid Leukaemia

Project description:We performed RNA-sequencing of normal haematopoietic stem cells and progenitor populations and of Leukemic Stem Cells in CD34- Acute Myeloid Leukaemia.

2016-06-22 | E-MTAB-2672 | biostudies-arrayexpress

GATA2 mitotic bookmarking is required for definitive hematopoiesis [scRNA-seq]

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2023-06-27 | GSE221691 | GEO

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