Modulation of NOTCH1 signaling in CLL and MCL cell lines
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ABSTRACT:
PROVIDER: PRJNA1242792 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant active NOTCH1 signaling is a key pathogenic factor in chronic lymphocytic leukemia (CLL), detectable in half of patients and associated with disease progression. While some cases of active NOTCH1 signaling can be explained by mutations in NOTCH1 or its regulators, like FBXW7, alternative mechanisms remain elusive. Here, we identified the deubiquitinase USP28 as regulator of NOTCH1 signaling in CLL. Notably, USP28 is located within the frequently deleted chr11q23 region and is deleted in 90% of del(11q) patients, resulting in its decreased expression. USP28 interacts with the NOTCH1 intracellular domain (NICD) independently of FBXW7 and the NICD-PEST domain, stabilizing NICD and enhancing NOTCH1 signaling. Integrating RBPJ-occupied genes in HG3 cells, RNA-Seq of USP28WT/KO cells and gene expression from del(11q) CLL patients, we identified 15 NOTCH1 target genes specifically dysregulated by USP28 and del(11q) potentially influencing CLL pathogenesis. Pharmacological inhibition of USP28 with the small molecule AZ1 suppressed NOTCH1 activation in primary CLL cells. AZ1 combined with the BCL-2 inhibitor venetoclax reduced CLL cell viability, particularly in samples with high NOTCH1 activity. Our findings highlight USP28 as promising therapeutic target and provide a rationale for combined inhibition of USP28 and BCL-2 in CLL patients with active NOTCH1 signaling.
2025-05-31 | GSE293100 | GEO
Project description:Microarray-based gene expression analysis identified genes differentially expressed in 3 MCL and 3 CLL cell lines compared to the lymphoblastoid non-tumor cell line LCL_WEI.
2010-06-03 | GSE16412 | GEO
Project description:Comparison of CLL and MCL primary cells obtained from a patient with MCL variant Richter syndrome
2016-07-13 | GSE84286 | 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:Functional studies to investigate gene mutations recurrent in B cell lymphoma have been hampered by the inability to genetically manipulate primary cells, attributed to low transduction efficacy and procedure-associated toxicity. Alternative approaches utilize cell lines and mouse models, which often only poorly represent the genomic complexity and biology of the primary malignancy. To overcome these limitations, we have developed a method to retrovirally transfer genes into primary malignant B cells with high transduction efficacy and minimal toxicity. Using this method, we investigated the functions of NOTCH1, the most commonly mutated gene in CLL, by generating isogenic primary tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-g signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+ T cells in vivo, further contributing to the poor clinical outcome of NOTCH1-mutated CLL and MCL
2022-08-26 | PXD024112 | Pride
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: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: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 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:Microarray-based gene expression analysis identified genes differentially expressed in 6 MCL and 18 CLL patient samples compared in independent analyses to CD19 selected healthy donor B-cell samples.
2010-06-03 | GSE16411 | GEO