BCL7A is silenced by hypermethylation to promote acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA940796 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23698659_1.fastq.gz | Fastqsanger.gz | |||
| SRR23698659_2.fastq.gz | Fastqsanger.gz | |||
| SRR23698660_1.fastq.gz | Fastqsanger.gz | |||
| SRR23698660_2.fastq.gz | Fastqsanger.gz | |||
| SRR23698661_1.fastq.gz | Fastqsanger.gz |
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Project description:Differential expression analysis was performed to determine pathways and genes altered after BCL7A expression restoration.
2023-04-07 | GSE226604 | GEO
Project description:BackgroundRecent massive sequencing studies have revealed that SWI/SNF complexes are among the most frequently altered functional entities in solid tumors. However, the role of SWI/SNF in acute myeloid leukemia is poorly understood. To date, SWI/SNF complexes are thought to be oncogenic in AML or, at least, necessary to support leukemogenesis. However, mutation patterns in SWI/SNF genes in AML are consistent with a tumor suppressor role. Here, we study the SWI/SNF subunit BCL7A, which has been found to be recurrently mutated in lymphomas, but whose role in acute myeloid malignancies is currently unknown.MethodsData mining and bioinformatic approaches were used to study the mutational status of BCL7A and the correlation between BCL7A expression and promoter hypermethylation. Methylation-specific PCR, bisulfite sequencing, and 5-aza-2'-deoxycytidine treatment assays were used to determine if BCL7A expression was silenced due to promoter hypermethylation. Cell competition assays after BCL7A expression restoration were used to assess the role of BCL7A in AML cell line models. Differential expression analysis was performed to determine pathways and genes altered after BCL7A expression restoration. To establish the role of BCL7A in tumor development in vivo, tumor growth was compared between BCL7A-expressing and non-expressing mouse xenografts using in vivo fluorescence imaging.ResultsBCL7A expression was inversely correlated with promoter methylation in three external cohorts: TCGA-LAML (N = 160), TARGET-AML (N = 188), and Glass et al. (2017) (N = 111). The AML-derived cell line NB4 silenced the BCL7A expression via promoter hypermethylation. Ectopic BCL7A expression in AML cells decreased their competitive ability compared to control cells. Additionally, restoration of BCL7A expression reduced tumor growth in an NB4 mouse xenograft model. Also, differential expression analysis found that BCL7A restoration altered cell cycle pathways and modified significantly the expression of genes like HMGCS1, H1-0, and IRF7 which can help to explain its tumor suppressor role in AML.ConclusionsBCL7A expression is silenced in AML by promoter methylation. In addition, restoration of BCL7A expression exerts tumor suppressor activity in AML cell lines and xenograft models.
| S-EPMC10026484 | biostudies-literature
Project description:Purpose：Examination of global gene expression of 14-day-old WT, bcl7a(brip3), bcl7b(brip4), bcl7a bcl7b(brip3 brip4), bcl7a bcl7b brm-3(brip3 brip4 brm-3) and bcl7a bcl7b brm-1(brip3 brip4 brm-1) seedlings under short day condition. Methods: Total RNA was extracted from 14-day-old Arabidopsis seedlings under short-day conditions using TRIzol reagent (Invitrogen) following the manufacturer's instructions. RNAs from three biological replicates was sequenced. separately at Novogene, using Illumina Hiseq X-Ten (Sequencing method: Hiseq-PE150). The paired-end RNA-seq reads were quantified by Salmon(Patro et al., 2017) (v1.5.1) with parameters -k 31 and --type quasi. Salmon index was generated using AtRTD2.fa as the reference transcriptome. The gene quantification files of all samples were used as inputs (TPM values) for differential gene expression analysis by DESeq2(Love et al., 2014) v3.10. To analyze differential gene expression in all samples, we used “parametric” Fit type, “ratio” method for estimate Size Factors and Wald significance test function provided by DESeq2. Conclusions: Our study represents the first detailed analysis of bcl7a(brip3), bcl7b(brip4), bcl7a bcl7b(brip3 brip4), bcl7a bcl7b brm-3(brip3 brip4 brm-3) and bcl7a bcl7b brm-1(brip3 brip4 brm-1) transcriptomes, with biologic replicates, generated by RNA-seq technology.
2024-01-03 | GSE215151 | GEO
Project description:Isocitrate dehydrogenases 1 and 2 (IDH1/2) are recurrently mutated in acute myeloid leukemia (AML), but their mechanistic role in leukemogenesis is poorly understood. The inhibition of TET enzymes by D-2-hydroxyglutarate (D-2-HG), which is produced by mutant IDH1/2 (mIDH1/2), has been suggested to promote epigenetic deregulation during tumorigenesis. In addition, mIDH also induces a differentiation block in various cell culture and mouse models. Here we analyze the genomic methylation patterns of AML patients with mIDH using Infinium 450K data from a large AML cohort and found that mIDH is associated with pronounced DNA hypermethylation at tens of thousands of CpGs. Interestingly, however, myeloid leukemia cells overexpressing mIDH, cells that were cultured in the presence of D-2-HG or TET2 mutant AML patients did not show similar methylation changes. In further analyses, we also characterized the methylation landscapes of myeloid progenitor cells and analyzed their relationship to mIDH-associated hypermethylation. Our findings identify the differentiation state of myeloid cells, rather than inhibition of TET-mediated DNA demethylation, as a major factor of mIDH-associated hypermethylation in AML. Furthermore, our results are also important for understanding the mode of action of currently developed mIDH inhibitors.
2017-09-15 | E-MTAB-6059 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: DNA methylation profiling Direct comparison of DNA methylation in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression. Two control groups are included: 8 CD34+ bone marrow samples from healthy donors and 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2010-05-07 | E-GEOD-14417 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Experiment Overall Design: Direct comparison of gene expression in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression, and with 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2009-01-24 | E-GEOD-14479 | biostudies-arrayexpress
Project description:Mutations in genes encoding the various subunits of the SWI/SNF chromatin remodeling complex are frequently observed in different human cancers. In diffuse large B-cell lymphoma (DLBCL), genetic changes in BCL7A, a subunit of the SWI/SNF complex, have been recently reported but the functional role of such genetic changes remains unknown. BCL7A mutations concentrate at the first exon and the most frequently mutated hotspot is the splice donor site of the first intron. By using in vitro and in vivo analyses, we show that restoration of BCL7A drives a tumor suppressor-like phenotype. Further, we found that splice site mutations block the tumor suppressor phenotype and prevent BCL7A from binding to the SWI/SNF complex. Finally, we identified that the SWI/SNF complex accumulates mutations in a third of DLBCL tumors, especially in the GCB subtype. These discoveries highlight the tumor suppressor role of BCL7A mutations in DLBCL, and suggest that the SWI/SNF complex is involved in DLBCL pathogenesis.
2020-10-21 | PXD014795 | Pride
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: DNA methylation profiling
2009-01-15 | GSE14417 | GEO
Project description:Mutations in genes encoding the various subunits of the SWI/SNF chromatin remodeling complex are frequently observed in different human cancers. In diffuse large B-cell lymphoma (DLBCL), genetic changes in BCL7A, a subunit of the SWI/SNF complex, have been recently reported but the functional role of such genetic changes remains unknown. BCL7A mutations concentrate at the first exon and the most frequently mutated hotspot is the splice donor site of the first intron. By using in vitro and in vivo analyses, we show that restoration of BCL7A drives a tumor suppressor-like phenotype. Further, we found that splice site mutations block the tumor suppressor phenotype and prevent BCL7A from binding to the SWI/SNF complex. Finally, we identified that the SWI/SNF complex accumulates mutations in a third of DLBCL tumors, especially in the GCB subtype. These discoveries highlight the tumor suppressor role of BCL7A mutations in DLBCL, and suggest that the SWI/SNF complex is involved in DLBCL pathogenesis.
2020-11-20 | GSE149277 | GEO
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: Gene expression profiling using arrays
2009-01-21 | GSE14479 | GEO