Genome-Wide Analysis of Acute Myeloid Leukemia Reveals Leukemia-Specific Methylome and Subtype-Specific Hypomethylation of Repeats
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE37022 | GEO | 2012/04/03
SECONDARY ACCESSION(S): PRJNA157503
REPOSITORIES: GEO
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Project description:Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq) has the potential to identify changes in DNA methylation important in cancer development. In order to understand the role of epigenetic modulation in the development of acute myeloid leukemia (AML) we have applied MeDIP-seq to the DNA of 12 AML patients and 4 normal bone marrows. This analysis revealed leukemia-associated differentially methylated regions that included gene promoters, gene bodies, CpG islands and CpG island shores. Two genes (SPHKAP and DPP6) with significantly methylated promoters were of interest and further analysis of their expression showed them to be repressed in AML. We also demonstrated considerable cytogenetic subtype specificity in the methylomes affecting different genomic features. Significantly distinct patterns of hypomethylation of certain interspersed repeat elements were associated with cytogenetic subtypes. The methylation patterns of members of the SINE family tightly clustered all leukemic patients with an enrichment of Alu repeats with a high CpG density (P<0.0001). We were able to demonstrate significant inverse correlation between intragenic interspersed repeat sequence methylation and gene expression with SINEs showing the strongest inverse correlation (R(2) = 0.7). We conclude that the alterations in DNA methylation that accompany the development of AML affect not only the promoters, but also the non-promoter genomic features, with significant demethylation of certain interspersed repeat DNA elements being associated with AML cytogenetic subtypes. MeDIP-seq data were validated using bisulfite pyrosequencing and the Infinium array.
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Project description:This SuperSeries is composed of the following subset Series: GSE28314: Genome-wide study of DNA methylation in AML by MeDIP-seq GSE34722: Gene expression profiling of Acute Myeloid Leukemia (AML) samples Refer to individual Series
2012-04-02 | E-GEOD-37022 | biostudies-arrayexpress
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.
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Project description:The E3 ubiquitin ligase and tumor suppressor APC/CCdh1 is crucial for cell cycle progression, development and differentiation in many cell types. However, little is known about the role of Cdh1 in hematopoiesis. Here we analyzed Cdh1 expression and function in malignant hematopoiesis. We found a significant decrease of Cdh1 in primary acute myeloid leukemia (AML) blasts compared to normal CD34+ cells. Thus, according to its important role in connecting cell cycle exit and differentiation, decreased expression of Cdh1 may be a mechanism contributing to the differentiation block in leukemogenesis. Indeed, knockdown (kd) of Cdh1 in HL-60 cell line (AML with maturation, FAB M2) led to less differentiated cells and a delay in PMA-induced differentiation. Acute promyelocytic leukemia (APL, FAB M3) is an AML subtype which is highly vulnerable to differentiation therapy with all-trans retinoic acid (ATRA). Accordingly, we found that APL is resistant to a Cdh1-kd mediated differentiation block. However, further depletion of Cdh1 in APL significantly reduced viability of leukemia cells upon ATRA-induced differentiation. Thus, low Cdh1 expression may be important in AML biology by contributing to the differentiation block and response to therapy depending on differences in the microenvironment and the additional genetic background.
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Project description:Highly heterogeneous acute myeloid leukemia (AML) exhibits dysregulated transcriptional programs. Transcription factor (TF) regulatory networks underlying AML subtypes have not been elucidated at single-cell resolution. Here, we comprehensively mapped malignancy-related TFs activated in different AML subtypes by analyzing single-cell RNA sequencing data from AMLs and healthy donors. We first identified six modules of regulatory networks which were prevalently dysregulated in all AML patients. AML subtypes featured with different malignant cellular composition possessed subtype-specific regulatory TFs associated with differentiation suppression or immune modulation. At last, we validated that ERF was crucial for the development of hematopoietic stem/progenitor cells by performing loss- and gain-of-function experiments in zebrafish embryos. Collectively, our work thoroughly documents an abnormal spectrum of transcriptional regulatory networks in AML and reveals subtype-specific dysregulation basis, which provides a prospective view to AML pathogenesis and potential targets for both diagnosis and therapy.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-09-20 | GSE108316 | GEO
Project description:BackgroundAcute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification.MethodsWe used bisulfite pyrosequencing to analyze the methylation status of four tet2-DMCs (SP140, MCCC1, EHMT1, and MTSS1) in a test group of 94 consecutive patients and a validation group of 92 consecutive patients treated with cytarabine-based chemotherapy. Data were analyzed with hierarchical clustering, Cox proportional hazards regression, and Kaplan-Meier analyses. All statistical tests were two-sided.ResultsIn the test cohort, hierarchical clustering analysis identified low levels of tet2-DMC methylation in 31 of 94 (33%) cases, and these had markedly longer overall survival (median survival 72+ vs 14 months, P = .002). Similar results were seen in the validation cohort. tet2-DMC-low status was shown to be an independent predictor of overall survival (hazard ratio = 0.29, P = .0002). In The Cancer Genome Atlas (TCGA) dataset where DNA methylation was analyzed by a different platform, tet2-DMC-low methylation was also associated with improved outcome (median survival = 55 vs 15 months, P = .0003) and was a better predictor of survival than mutations in TET2, IDH1, or IDH2, individually or combined.ConclusionsLow levels of tet2-DMC methylation define a subgroup of AML that is highly curable and cannot be identified solely by genetic and cytogenetic analyses.
| S-EPMC4862435 | biostudies-literature
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 | GSE108246 | GEO
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
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 | GSE108266 | GEO