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Gene expression profiling of CLL cells with hyperactivated Notch1 compared to control CLL cells [RNA-seq]

ABSTRACT: NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE147836 | GEO | 2020/12/19

REPOSITORIES: GEO

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Chromatin profiling of CLL cells with hyperactivated Notch1 compared to control CLL cells [ATAC-seq]

Project description:NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.

2020-12-19 | GSE160508 | GEO

RBPJ and H3K27ac chromatin IP with sequencing of CLL cells with hyperactivated Notch1 compared to control CLL cells [ChIP-seq]

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Active AKT Signaling triggers CLL towards Richter's transformation via over-activation of Notch1

Project description:Richter's syndrome (RS) is an aggressive transformation of Chronic Lymphocytic Leukaemia (CLL) frequently due to TP53, CDKN2, MYC or NOTCH1 mutations. whereas a significant proportion displays no specifically acquired driver mutation. We observe constitutive AKT phosphorylation not only in high-risk CLL patients harbouring p53 and NOTCH mutations but also in numerous RS patients. Consistently, genetic over-activation of AKT within the Eµ-TCL1 CLL mouse model results in a high-grade lymphoma phenotype of Richters syndrome. Multiomics assessment of our novel mouse model revealed a S100 defined subcluster of highly proliferative lymphoma cells developing from indolent CLL-like B-cells as a consequence of sudden NOTCH activation being fueled by enhanced NOTCH ligand exposure from T-cells in the microenvironment. Our data link AKT and NOTCH signaling in patient samples, genomic alterations, phosphoproteome and single-cell transcriptome profiles. Collectively, we have identified active AKT as a causative transforming pathway of indolent CLL towards aggressive RS thus providing novel mechanistic insights into the molecular understanding of RS.

2021-02-25 | PXD017457 | Pride

Gene expression profile of primary CLL cells transduced with a retrovirus expressing mutated NOTCH1

Project description:In CLL, NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the gene expression profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs cells transduced with an empty vector. Additionally, patients with the Trisomy 12 abnormality are included in this study to clarify the role of the mutations in this specific sub-group of CLL patients that are strongly associated with NOTCH1 mutations.

2022-09-08 | GSE150584 | GEO

Gene expression study in WT and NOTCH1 mutated CLL cells.

Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL.

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Gene expression study in WT and NOTCH1 mutated CLL cells.

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Gene expression profile of primary CLL cells transduced with a mutated form on NOTCH1 following IgM stimulation

Project description:In CLL, NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. Data suggests a link between BCR activation and NOTCH1 signalling so the main goal of this study is to compare the gene expression profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs cells transduced with an empty vector following IgM stimulation.

2022-09-08 | GSE150595 | GEO

Identification of genes induced by NOTCH1 in a chronic lymphocytic leukaemia (CLL) cell line and tracking of these genes in primary CLL patients

Project description:NOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease.

2017-03-24 | GSE92626 | GEO

Histone H3 lysine 27 acetylation (H3K27ac) profile of primary CLL cells transduced with a retrovirus expressing mutated NOTCH1

Project description:In chronic lymphocytic leukemia (CLL), NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the chromatin activation profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs. cells transduced with an empty vector. Additionally, patients with the Trisomy 12 abnormality are included in this study to clarify the role of the mutations in this specific sub-group of CLL patients that are strongly associated with NOTCH1 mutations.

2022-09-08 | GSE166727 | GEO

Identification of NOTCH1 bound genes in chronic lymphocytic leukaemia (CLL) cells

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