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3D chromatin hubs as regulatory units of identity and survival in acute T-cell leukemia [RNA-seq]

ABSTRACT: Cancer progression is associated with genetic and epigenetic aberrations that affect chromatin 3D organization in the nucleus. Changes in loop extrusion or phase separation alter the relationships between enhancer and promoter elements, defining novel gene expression programs that are selected to promote growth and survival. Here, we provide an integrative approach based on chromatin conformation, accessibility and transcription, further validated by CRISPR interference screenings in order to identify chromatin topologies relevant to different subtypes of T-cell leukemia, namely T-ALL and ETP-ALL. By focusing on highly interconnected elements, we characterized 3D hubs as headquarters of leukemia progression and identity, demonstrating that oncogenes and disease markers are regulated by multiple cis-regulatory regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243914 | GEO | 2023/09/25

REPOSITORIES: GEO

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3D chromatin hubs as regulatory units of identity and survival in acute T-cell leukemia [hiChIP]

Project description:Cancer progression is associated with genetic and epigenetic aberrations that affect chromatin 3D organization in the nucleus. Changes in loop extrusion or phase separation alter the relationships between enhancer and promoter elements, defining novel gene expression programs that are selected to promote growth and survival. Here, we provide an integrative approach based on chromatin conformation, accessibility and transcription, further validated by CRISPR interference screenings in order to identify chromatin topologies relevant to different subtypes of T-cell leukemia, namely T-ALL and ETP-ALL. By focusing on highly interconnected elements, we characterized 3D hubs as headquarters of leukemia progression and identity, demonstrating that oncogenes and disease markers are regulated by multiple cis-regulatory regions.

2023-09-25 | GSE243913 | GEO

Transcriptional circuits that regulate early T cell precursor acute leukemia (RNA-seq)

Project description:The discovery of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) was based on expression of stem cell genes that are characteristic of mouse ETP cells, the most primitive multipotent cells in the thymus. Using complementary mouse and human genetic models and genome-wide expression and chromatin profiling integrated with 3D chromatin mapping, we show that the PIAS-like coactivator ZMIZ1 promotes immature T-ALL proliferation by recruiting the transcription factor MYB in feedforward circuits to cooperatively induce MYCN, MEF2C, and BCL2, which were recently associated with the high-risk bone marrow progenitor (BMP-like) subset.

2023-07-05 | GSE235685 | GEO

Transcriptional circuits that regulate early T cell precursor acute leukemia [HiChIP]

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Transcriptional circuits that regulate early T cell precursor acute leukemia [Hi-C]

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Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus

Project description:Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

2023-03-29 | GSE223132 | GEO

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

Project description:Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early-T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient’s ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-Seq documented that GSI downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSI was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T cell type. H3K27ac superenhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited. RNAseq and H3K27Ac ChIP seq of primary leukemic blasts treated in vitro with vehicle control or gamma-secretase inhibitor BMS-096024

2015-07-29 | E-GEOD-71414 | biostudies-arrayexpress

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

2015-07-29 | GSE71414 | GEO

CEBPA phase separation links transcriptional activity and 3D chromatin hubs

Project description:Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell to macrophage transdifferentiation. A large intrinsically disordered region (IDR) enables CEBPA to undergo in vitro phase separation and to co-condense with transcriptional partners, which is at least partially mediated by aromatic residues. Furthermore, CEBPA forms visible nuclear condensates in transdifferentiating B cells that co-localize with co-activator condensates and recover rapidly upon photobleaching. Finally, native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors (GMPs), liver cells and trophectoderm cells also reveal nuclear CEBPA condensates and long-range 3D chromatin hubs at CEBPA-bound regions. These findings support a model in which CEBPA acts as a 3D genome structural organizer and suggest that this effect is mediated at least in part by its phase-separation capacity.

2023-07-24 | GSE221167 | GEO

Gene expression profiling of P53/R26 +/+ (n=2) versus P53/R26-Zeb2tg/tg (n=3) thymic tumors

2015-05-23 | GSE62653 | GEO

Gene expression profiling of P53/R26 +/+ (n=2) versus P53/R26-Zeb2tg/tg (n=3) thymic tumors

Project description:Early T-cell precursor leukemia (ETP-ALL) is a high-risk subtype of human leukemia that is poorly understood at the molecular level. Here, we report translocations targeting the zinc finger E-box binding transcription factor ZEB2 as a new and recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression perturbs normal T-cell differentiation and initiates T-cell leukemia. Moreover, Zeb2 driven mouse leukemia exhibit some features of the human immature/ETPALL gene expression signature, as well as an enhanced leukemia-initiation potential and activated JAK/STAT signaling through transcriptional activation of IL7R. This study reveals ZEB2 as a novel oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2 driven mouse model. Conditional Zeb2 knockin mouse model was developed and crossed into p53 null background. Murine T-cell leukemia/lymphoma tumors developed both in the p53 null control and the p53 null Zeb2 transgenic group. In this experiment, gene expression profiling was performed on these murine leukemias to determine the transcriptional program associated with sustained Zeb2 expression in the context of P53 null driven murine T cell leukemogenesis.

2015-05-23 | E-GEOD-62653 | biostudies-arrayexpress

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