Genomic Alterations in High-risk CLL Frequently Affect Cell Cycle Key Regulators and NOTCH1‑regulated Transcription.
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PROVIDER: PRJNA542690 | ENA |
REPOSITORIES: ENA
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Project description:To identify genomic alterations contributing to the pathogenesis of high‑risk chronic lymphocytic leukemia (CLL) beyond the well‑established role of TP53 aberrations, we comprehensively analyzed 146 high‑risk CLL cases by single‑nucleotide polymorphism (SNP)‑arrays and targeted next‑generation sequencing including 75 relapsed/refractory and 71 treatment‑naïve high‑risk cases from prospective clinical trials. Increased genomic complexity was a hallmark of relapsed/refractory and treatment‑naïve high‑risk CLL, and was associated with TP53 and ATM dysfunction. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both of these copy number alterations (CNAs) affected key regulators of cell cycle progression, namely c‑MYC and CDKN2A/B. Gains in 8q24.21 were either focal gains in a c‑MYC enhancer region or larger gains directly affecting the c‑MYC locus, but only the latter type was highly enriched in relapsed/refractory CLL (17%). Loss of CDKN2A/B was found frequently to co‑occur with gain of c‑MYC and in this combination it was likely associated with Richter transformation. In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and c‑MYC gene transcription and found de‑repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the pathogenesis of high‑risk CLL by defining novel recurrent CNAs and identifying alterations that likely contribute to disease refractoriness.
2020-05-06 | GSE131114 | GEO
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 | GSE92701 | GEO
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
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.
2016-03-01 | GSE75122 | GEO
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. Constitutive gene expression in CLL cells bearing or not NOTCH1 mutation (c.7541_7542delCT). Five samples were selected for each category (WT vs MUT).
2016-03-01 | E-GEOD-75122 | biostudies-arrayexpress
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
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
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
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 | GSE147836 | GEO
Project description:Mutations of SF3B1 in CLL induce alternative splicing in multiple transcripts, including DVL2. DVL2 in turn can act as a negative regulator of NOTCH1 signaling. Gene Expression Profile (GEP) was used to investigate the activation of the NOTCH1 pathway in presence of alternatively spliced DVL2.
2019-09-07 | GSE137024 | GEO