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Gene expression profiling of LSK cells with hyperactivated Notch1 and/or Tcf7 knock-out [RNA-seq]

ABSTRACT: NOTCH1 is a well-established lineage specifier for T cells and amongst the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology allowing for aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered an additional evolutionarily conserved Tcf1-regulated enhancer element, in the distal Myc-enhancer, which is important for the transition of pre-leukemic cells to full-blown disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE169116 | GEO | 2022/01/21

REPOSITORIES: GEO

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Chromatin accessibility analysis of human cord blood cells with hyperactivated Notch1 [ATAC-seq_human]

Project description:NOTCH1 is a well-established lineage specifier for T cells and amongst the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology allowing for aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered an additional evolutionarily conserved Tcf1-regulated enhancer element, in the distal Myc-enhancer, which is important for the transition of pre-leukemic cells to full-blown disease.

2022-01-21 | GSE169119 | GEO

3D chromatin topography of LSK cells with hyperactivated Notch1 and/or Tcf7 knock-out [HiC-seq]

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Chromatin accessibility profiling of LSK cells with hyperactivated Notch1 and/or Tcf7 knock-out [ATAC-seq_mouse]

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RNA-Sequencing experiment for effects of PKF115-584 treatment on four T-ALL cell lines (RPMI8402, HPB-ALL, Jurkat, CCRF-CEM).

Project description:Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of β-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of β-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of β-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required β-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1.

2018-01-31 | GSE69157 | GEO

ChIP-Sequencing experiment for N1IC and β-Catenin in Jurkat T-ALL cells.

Project description:Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. Using multiple in vivo and in vitro T-ALL models we here demonstrate that β-Catenin is essential for Notch-driven T-cell leukemic initiation. Transcriptome analyses of leukemic initiating cells revealed a switch in β-Catenin activity that was Notch-context dependent. Moreover, ChIP-seq coupled with RNA-Seq in human Notch-active T-ALL showed that leukemic β-Catenin was independent of canonical LEF/TCF partners, and instead depended on direct association with Notch or ZBTB33/Kaiso for gene activation. The functional relevance of this mechanism is exemplified by the MYC 3´enhancer that requires β-Catenin and Notch1 recruitment to induce MYC expression. Finally, we demonstrate that pharmacological inhibition of β-Catenin with PKF115-584 prevented and partially reverted leukemogenesis induced by active Notch1.

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Expression data from c-Myc+ Notch1 T-ALL initiating cells

Project description:Missense FBXW7 mutations are prevalent in various tumors, including T-cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. We show here that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes, but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Three independent Notch1 T-ALL were derived on c-Myc-GFP background and sorted from the spleen of leukemic mice on the basis of GFP expression for RNA extraction and hybridization on Affymetrix microarrays

2013-05-10 | E-GEOD-46797 | biostudies-arrayexpress

Gene expression analyses of GFP+ sorted, lineage depleted (Lin-) bone marrow (BM) cells from wild-type or VavCre+β-Catenin-KO mice infected with pMIG-GFP (control) or pMIG-N1IC-GFP retrovirus.

Project description:Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. Using multiple in vivo and in vitro T-ALL models we here demonstrate that β-Catenin is essential for Notch-driven T-cell leukemic initiation. Transcriptome analyses of leukemic initiating cells revealed a switch in β-Catenin activity that was Notch-context dependent. Moreover, ChIP-seq coupled with RNA-Seq in human Notch-active T-ALL showed that leukemic β-Catenin was independent of canonical LEF/TCF partners, and instead depended on direct association with Notch or ZBTB33/Kaiso for gene activation. The functional relevance of this mechanism is exemplified by the MYC 3´enhancer that requires β-Catenin and Notch1 recruitment to induce MYC expression. Finally, we demonstrate that pharmacological inhibition of β-Catenin with PKF115-584 prevented and partially reverted leukemogenesis induced by active Notch1. These microarray data show the transcriptional activities of N1IC and β-Catenin in wild-type or leukemic initiating cell (LIC) contexts in N1IC-transduced adult Lineage-depleted BM cells.

2023-01-01 | GSE69155 | GEO

Gene expression analyses of E14.5 fetal liver Lin-Sca1+ckit+ (LSK) cells from wild-type, β-Catenin-KO, N1IC+ and N1IC+β-Catenin-KO embryos.

Project description:Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. Using multiple in vivo and in vitro T-ALL models we here demonstrate that β-Catenin is essential for Notch-driven T-cell leukemic initiation. Transcriptome analyses of leukemic initiating cells revealed a switch in β-Catenin activity that was Notch-context dependent. Moreover, ChIP-seq coupled with RNA-Seq in human Notch-active T-ALL showed that leukemic β-Catenin was independent of canonical LEF/TCF partners, and instead depended on direct association with Notch or ZBTB33/Kaiso for gene activation. The functional relevance of this mechanism is exemplified by the MYC 3´enhancer that requires β-Catenin and Notch1 recruitment to induce MYC expression. Finally, we demonstrate that pharmacological inhibition of β-Catenin with PKF115-584 prevented and partially reverted leukemogenesis induced by active Notch1. These microarray data show the transcriptional activities of N1IC and β-Catenin in wild-type or leukemic initiating cell (LIC) contexts in E14.5 FL LSK cells.

2023-01-01 | GSE69154 | GEO

Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia

Project description:Notch is needed for T cell development and is a common oncogenic driver in T cell acute lymphoblastic leukemia. Myc is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region is comprised of an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of Brd4, a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3’ enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.

2014-11-11 | GSE61504 | GEO

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