Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA272133 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
2016-02-01 | GSE72298 | GEO
Project description:T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
2016-02-01 | GSE72299 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we assayed for genome-wide localization of JMJD3 enrichment. This piece of data was further integrated to expression changes using RNA sequencing as well as ChIP-Sequencing analysis of H3K27me3 upon genomic/genetic knock-down or chemical inhibition of JMJD3 and UTX. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX plays a tumor suppressor role. JMJD3 ChIP: 10 million cells were used for the ChIP and precipitated using 10micrograms of antibody (abgent, AP1022a) against human JMJD3.
2014-10-01 | E-GEOD-56694 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we conduct expression analysis in NOTCH1-IC-induced tumors in Utx wild-type (Utx+/+ or Utx+/Y) and knockout (Utx-/Y) background. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to characterize the hitherto understudied role of Utx as an oncogenic facilitator in leukemia and the contrasting expression signatures between JMJD3 and UTX in this disease.
2014-10-01 | GSE56690 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we assayed for genome-wide localization of JMJD3 enrichment. This piece of data was further integrated to expression changes using RNA sequencing as well as ChIP-Sequencing analysis of H3K27me3 upon genomic/genetic knock-down or chemical inhibition of JMJD3 and UTX. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX plays a tumor suppressor role.
2014-10-01 | GSE56694 | GEO
Project description:In many cancers, critical oncogenes are driven from large regulatory elements, called super-enhancers, which recruit much of the cellM-bM-^@M-^Ys transcriptional apparatus and are defined by extensive H3K27 acetylation. We found that in T-cell acute lymphoblastic leukemia (T-ALL), somatic heterozygous mutations introduce MYB binding motifs in a precise noncoding site, which nucleate a super-enhancer upstream of the TAL1 oncogene. Further analysis of genome-wide binding identified MYB and its histone acetylase binding partner CBP as core components of the TAL1 complex and of the TAL1-mediated feed-forward auto-regulatory loop that drives T-ALL. Furthermore, MYB and CBP occupy endogenous MYB binding sites in the majority of super-enhancer sites found in T-ALL cells. Thus, our study reveals a new mechanism for the generation of super-enhancers in malignant cells involving the introduction of somatic indel mutations within non-coding sequences, which introduce aberrant binding sites for the MYB master transcription factor. ChIP-Seq for transcription factors and co-factors in T cell acute lymphoblastic leukemia cell lines
2014-11-13 | E-GEOD-59657 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we conduct expression analysis in NOTCH1-IC-induced tumors in Utx wild-type (Utx+/+ or Utx+/Y) and knockout (Utx-/Y) background. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to characterize the hitherto understudied role of Utx as an oncogenic facilitator in leukemia and the contrasting expression signatures between JMJD3 and UTX in this disease. Whole RNA was extracted from 1-5 million primary cells from Notch1-IC-expressing (sorted populations of) mouse T-ALL tumors using the RNAeasy kit (Qiagen) according to the manufacturer’s protocol. Poly-A+ (magnetic oligodT-containing beads (Invitrogen)) or Ribominus RNA was used for library preparation. cDNA preparation and strand-specific library construction was performed using the dUTP method. Libraries were sequenced on the Illumina HiSeq 2000 using 50bp single-read method. Differential gene expression analysis was performed between knockout vs wild-type background samples. Analysis was performed using DEGseq package leading to very similar conclusions.
2014-10-01 | E-GEOD-56690 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we chemically inhibited the H3K27me3 demethylase JMJD3 using the GSKJ4 inhibitor and assayed for genome-wide changes in H3K27me3 and JMJD3 enrichment. This piece of data was further integrated to expression changes using RNA sequencing as well as ChIP-Sequencing analysis of H3K27me3 upon genomic knock-down of JMJD3 and UTX. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Histone ChIP: Half to one million cells were treated with micrococcal nuclease (MNASE) to generate mononucleosomal particles and an adaptation of the Upstate ChIP protocol was used.
2014-10-01 | E-GEOD-56693 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we abrogated the expression of JMJD3 (KDM6B) and UTX (KDM6A) H3K27me3 demethylases in human T-ALL lines and assayed for genome-wide changes in H3K27me3 levels. This piece of data was further integrated to expression changes using RNA sequencing in the same cells as well as ChIP-Sequencing analysis of H3K27me3 and JMJD3 genome-wide analysis from treatment of T-ALL lines with the GSKJ4 inhibitor. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Half to one million cells were treated with micrococcal nuclease (MNASE) to generate mononucleosomal particles and an adaptation of the Upstate ChIP protocol was used.
2014-10-01 | E-GEOD-56692 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we chemically inhibited the H3K27me3 demethylase JMJD3 using the GSKJ4 inhibitor and assayed for genome-wide changes in H3K27me3 and JMJD3 enrichment. This piece of data was further integrated to expression changes using RNA sequencing as well as ChIP-Sequencing analysis of H3K27me3 upon genomic knock-down of JMJD3 and UTX. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3 as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role.
2014-10-01 | GSE56693 | GEO