WES of TCL1 mouse model of CLL
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB42362 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5105460_1.fastq.gz | Fastqsanger.gz | |||
| ERR5105460_2.fastq.gz | Fastqsanger.gz | |||
| ERR5105470_1.fastq.gz | Fastqsanger.gz | |||
| ERR5105470_2.fastq.gz | Fastqsanger.gz | |||
| ERR5105480.fastq.gz | Fastqsanger.gz |
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Project description:Predicting disease progression in chronic lymphocytic leukemia (CLL) remains challenging particularly in patients with Rai Stage 0/I disease that have an unmutated immunoglobulin heavy chain variable region (UM IGHV). Even though patients with UM IGHV have a poor prognosis and generally require earlier treatment, not all UM IGHV patients experience more rapid disease progression with some remaining treatment free for many years. This observation suggests biologic characteristics other than known prognostic factors influence disease progression. Alterations in long non-coding RNA (lncRNA) expression levels have been implicated in diagnosis and prognosis of various cancers, however, their role in disease progression of early Rai stage UM CLL is unknown. Here we use microarray analysis to compare lncRNA and mRNA profiles of Rai 0/I UM IGHV patients who progressed in <2 years relative to patients who had not progressed for >5 years. Over 1300 lncRNAs and 940 mRNAs were differentially expressed (fold change ≥ 2.0; p-value ≤ 0.05). Of interest, the differentially expressed lncRNAs G047155, TCAM1P, and uc.436, have known associated genes that have been linked to CLL. Thus, our study reveals differentially expressed lncRNAs in progressive early stage CLL requiring therapy versus indolent early Rai stage UM CLL. These lncRNAs have the potential to impact relevant biological processes and pathways that influence clinical outcome in CLL.
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Project description:Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib represent an effective strategy for treatment of chronic lymphocytic leukemia (CLL), although ~30% of patients eventually undergo disease progression. Here we investigated the long-term modulation of the CXCR4dim/CD5bright proliferative fraction (PF) and the CXCR4bright/CD5dim resting fraction (RF) in CLL samples, and their correlation with therapeutic outcome and emergence of ibrutinib resistance. Longitudinal tracking by flow cytometry revealed that PF, initially suppressed by ibrutinib, reappeared upon early disease progression suggesting that PF evaluation could represent a sensitive and specific marker of CLL progression upon ibrutinib treatment. Transcriptomic analyses of PF at progression revealed similar proliferation signatures between pre- and post-treatment PF, demonstrating the emergence upon progression of a newly proliferating cell population.
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Project description:Purpose: The chromosomal deletion 11q affects biology and clinical outcome in CLL but del11q-deregulated genes remain incompletely characterized. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (~10-fold higher mean levels than other genomic categories) was confirmed by Q-PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through FACS, compared with measurements in normal CD19+ B-cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels.
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Project description:RNA-sequencing was used to determine gene expression of 4 Eµ-TCL1 (control) and 4 Eµ-TCL1 Zap70-ki mice which developed CLL.
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Project description:Purpose: The chromosomal deletion 11q affects biology and clinical outcome in CLL but del11q-deregulated genes remain incompletely characterized. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (~10-fold higher mean levels than other genomic categories) was confirmed by Q-PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through FACS, compared with measurements in normal CD19+ B-cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. We have employed integrated genomic profiling approaches upon CLL cases with and without del11q to identify 11q-relevant genes. Included are 10 primary human cases with del11q and 9 cases without del11q
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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.
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2021-09-24 | PXD022198 | 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.
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