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CLL in Em-TCL1 mice provides a biologically relevant model to unravel and reverse immune deficiency in human cancer.

ABSTRACT: Immune deficiency is common in cancer, but the biological basis for this and ways to reverse it remains elusive. Here we present a mouse model of B cell chronic lymphocytic leukemia (CLL) that recapitulates changes in the non-malignant circulating T cells seen in patients with this illness.1 To validate this model, we examined changes in T cell gene expression, protein expression and function in Em-TCL1 transgenic mice as they developed CLL 2,3 and demonstrate that development of CLL in these transgenic mice is associated with changes in impaired T cell function and in gene expression in CD4 and CD8 T cells similar to those observed in patients with this disease. Infusion of CLL cells into non-leukemia bearing Em-TCL1 mice rapidly induces these changes, demonstrating a causal relationship between leukemia and the induction of T cell changes. This model allows dissection of the molecular changes induced in CD4 and CD8 T cells by interaction with leukemia cells and further supports the concept that cancer results in complex abnormalities in the immune microenvironment. Gene expression profiling was performed to determine whether Em-TCL1 murine model of chronic lymphocytic leukemia (CLL) mimics T cell defects induced by CLL cells in patients with CLL. Keywords: comparative gene expression profiling analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE8836 | GEO | 2007/12/01

SECONDARY ACCESSION(S): PRJNA102173

REPOSITORIES: GEO

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Transcription profiling of mouse model of CLL in Em-TCL1 mice provides a biologically relevant model to unravel and reverse immune deficiency in human cancer.

Project description:Immune deficiency is common in cancer, but the biological basis for this and ways to reverse it remains elusive. Here we present a mouse model of B cell chronic lymphocytic leukemia (CLL) that recapitulates changes in the non-malignant circulating T cells seen in patients with this illness.1 To validate this model, we examined changes in T cell gene expression, protein expression and function in Em-TCL1 transgenic mice as they developed CLL 2,3 and demonstrate that development of CLL in these transgenic mice is associated with changes in impaired T cell function and in gene expression in CD4 and CD8 T cells similar to those observed in patients with this disease. Infusion of CLL cells into non-leukemia bearing Em-TCL1 mice rapidly induces these changes, demonstrating a causal relationship between leukemia and the induction of T cell changes. This model allows dissection of the molecular changes induced in CD4 and CD8 T cells by interaction with leukemia cells and further supports the concept that cancer results in complex abnormalities in the immune microenvironment. Gene expression profiling was performed to determine whether Em-TCL1 murine model of chronic lymphocytic leukemia (CLL) mimics T cell defects induced by CLL cells in patients with CLL. Experiment Overall Design: CD4 T cells and CD8 T cells were obtained from spleens of B6C3 and Em-TCL1 transgenic murine model of CLL or from peripheral blood mononuclear cells of previously untreated patients with CLL and healthy individuals (Pubmed ID: 15965501). Gene expression profiling was performed using total RNA and the data were analysed to compare gene expression profile of CLL to healthy within or between the species.

2008-06-17 | E-GEOD-8836 | biostudies-arrayexpress

Nanda2013 - B cell chronic lymphocytic leukemia A model with immune response

Project description:B cell chronic lymphocytic leukemia - A model with immune response Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3, 1. Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India 2. Department of Mathematics, Harvey Mudd College, Claremont, CA 91711 3. Department of Mathematics, Pomona College, Claremont, CA, 91711, United States Abstract B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based. Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.

2020-01-09 | MODEL2001090002 | BioModels

Expression data for Tcl1 tg mice compared to CD44ΔB Tcl1 tg mice

Project description:Tcl1 tg mice develop a chronic lymphocytic leukemia (CLL) -like disease. To investigate the contribution of the adhesion molecule CD44 to CLL pathophysiology, we developed a CD19Cre CD44flox/flox Tcl1 tg mouse with a B cell specific CD44 deficiency (CD44ΔB Tcl1 tg). We used the Clariom S mouse microarray from Affymetrix to investigate transcriptional differeneces between Tcl1 tg and CD44ΔB Tcl1 tg mice

2018-01-13 | GSE109121 | GEO

Expression data of CLL cells with and without NFAT2 expression

Project description:Chronic lymphocytic leukemia (CLL) is a disorder of mature B cells. Most patients are characterized by indolent disease and an anergic phenotype of their leukemia cells which refers to a state of unresponsiveness to B cell receptor stimulation. Using the Eµ-TCL1 mouse model, we show that B cell-specific ablation of NFAT2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and histological transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependant genes employing microarray technology.

2016-08-30 | GSE86210 | GEO

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [RNA-seq]

Project description:In B-cell chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival and expansion. Using the Eμ-TCL1 mouse model, we demonstrate that leukemic cells induce the activation of retinoid acid synthesis and signaling in stromal cells of the lymphoid microenvironment.

2018-05-09 | GSE111612 | GEO

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [microarray]

2018-05-09 | GSE111470 | GEO

Transcriptomic characterization of CXCR4C1013G and Eµ-TCL1;CXCR4C1013G CD19+ B cells

Project description:Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation furthermore resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype. Here we make available the transcriptomic data of CD19+ B cells from bone marrow and spleen of 6-week-old WT, CXCR4C1013G, Eµ-TCL1 and Eµ-TCL1;CXCR4C1013G mice.

2021-06-27 | GSE178959 | GEO

Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B cell activation and proliferation

Project description:In human chronic lymphocytic leukemia (CLL) pathogenesis B cell antigen receptor signaling seems important for leukemia B cell ontogeny, whereas the microenvironment influences B cell activation, tumor cell lodging and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells (FDCs) confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.

2014-09-01 | GSE60925 | GEO

Expression data from CD19-positive splenic B cells isolated from 1-month old ID4+/-TCL1-tg and ID4+/+TCL1-tg mice

Project description:The function of ID4 in CLL development was studied in vivo using TCL1 transgenic mouse model that develop leukemia similar to human CLL. TCL1 mice with ID4 single knockout gene have accelerated CLL progression. Results from the animal study suggest ID4 as a tumor suppressor gene that might regulate cell proliferation and apoptosis in B lymphocytes. Gene expression in CD19-positive splenic B cells collected from 1-month old ID4+/-TCL1-tg and ID4+/+TCL1-tg mice was compared by microarray, the goal is to find ID4-regulated genes involved in CLL development.

2010-11-04 | E-GEOD-25100 | biostudies-arrayexpress

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

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