Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia.

ABSTRACT: Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.

SUBMITTER: Ozturk S

PROVIDER: S-EPMC8071295 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model.

Project description:The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes. Molecular analyses revealed that miR-181b not only affected the expression of TCL1, Bcl2 and Mcl1 anti-apoptotic proteins, but also reduced the levels of Akt and phospho-Erk1/2. Notably, a siRNA anti-TCL1 could similarly down-modulate TCL1, but exhibited a reduced or absent activity in other relevant proteins, as well as a reduced effect on cell apoptosis and viability. In vivo studies demonstrated the capability of miR-181b to reduce leukemic cell expansion and to increase survival of treated mice.These data indicate that miR-181b exerts a broad range of actions, affecting proliferative, survival and apoptotic pathways, both in mice and human cells, and can potentially be used to reduce expansion of B-CLL leukemic cells.

| S-EPMC4637322 | biostudies-literature

The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia.

Project description:Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1α are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1α being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL.

| S-EPMC8466120 | biostudies-literature

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.

Project description:Ibrutinib (Imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.

| S-EPMC4103574 | biostudies-other

Evidence for Non-Cancer-Specific T Cell Exhaustion in the Tcl1 Mouse Model for Chronic Lymphocytic Leukemia.

Project description:The reinvigoration of anti-cancer immunity by immune checkpoint therapies has greatly improved cancer treatment. In chronic lymphocytic leukemia (CLL), patients as well as in the Tcl1 mouse model for CLL, PD1-expressing, exhausted T cells significantly expand alongside CLL development; nevertheless, PD1 inhibition has no clinical benefit. Hence, exhausted T cells are either not activatable by simple PD1 blocking in CLL and/or only an insufficient number of exhausted T cells are CLL-specific. In this study, we examined the latter hypothesis by exploiting the Tcl1 transgenic CLL mouse model in combination with TCR transgene expression specific for a non-cancer antigen. Following CLL tumor development, increased PD1 levels were detected on non-CLL specific T cells that seem dependent on the presence of (tumor-) antigen-specific T cells. Transcriptome analysis confirmed a similar exhaustion phenotype of non-CLL specific and endogenous PD1pos T cells. Our results indicate that in the CLL mouse model, a substantial fraction of non-CLL specific T cells becomes exhausted during disease progression in a bystander effect. These findings have important implications for the general efficacy assessment of immune checkpoint therapies in CLL.

| S-EPMC8268419 | biostudies-literature

TCL1 transgenic mice as a model for CD49d-high chronic lymphocytic leukemia.

Project description: Not available

| S-EPMC7449868 | biostudies-literature

Chronic lymphocytic leukemia therapy: new targeted therapies on the way.

Project description:IntroductionThe critical role of the tissue microenvironment and B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development.Areas coveredIn this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings.Expert opinionIbrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway.

| S-EPMC4955400 | biostudies-literature

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression.

Project description:B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V(H)) and indolent (showing low ZAP-70 expression and mutated IgH V(H)). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19(+) B cells. To study the role of miR-29 in B-CLL, we generated Emu-miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5(+) population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5(+) B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5(+) B-cell population to approximately 100%. Of 20 Emu-miR-29 transgenic mice followed to 24-26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.

| S-EPMC2901490 | biostudies-literature

TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.

Project description:B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3'UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19(+) cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression.

| S-EPMC4343115 | biostudies-literature

Accelerated progression of chronic lymphocytic leukemia in E?-TCL1 mice expressing catalytically inactive RAG1.

Project description:Chronic lymphocytic leukemia (CLL) is a prevalent B-cell neoplasia that is often preceded by a more benign monoclonal CD5(+) B-cell lymphocytosis. We previously generated transgenic mice expressing catalytically inactive RAG1 (dominant-negative recombination activating gene 1 [dnRAG1] mice) that develop an early-onset indolent CD5(+) B-cell lymphocytosis attributed to a defect in secondary V(D)J rearrangements initiated to edit autoreactive B-cell receptor (BCR) specificity. Hypothesizing that CD5(+) B cells in these animals represent potential CLL precursors, we crossed dnRAG1 mice with CLL-prone E?-TCL1 mice to determine whether dnRAG1 expression in E?-TCL1 mice accelerates CLL onset. Consistent with this hypothesis, CD5(+) B-cell expansion and CLL progression occurred more rapidly in double-transgenic mice compared with E?-TCL1 mice. Nevertheless, CD5(+) B cells in the 2 mouse strains exhibited close similarities in phenotype, immunoglobulin gene usage, and mutation status, and expression of genes associated with immune tolerance and BCR signaling. Gene expression profiling further revealed a potential role for prolactin signaling in regulating BCR editing. These results suggest a model in which benign accumulation of CD5(+) B cells can be initiated through a failure to successfully edit autoreactive BCR specificity and may, in turn, progress to CLL upon introduction of additional genetic mutations.

| S-EPMC3700393 | biostudies-literature

p66Shc deficiency in the E?-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape.

Project description:The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the E?-TCL1 mouse model of chronic lymphocytic leukemia. We showed that E?-TCL1/p66Shc-/- mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in E?-TCL1 mice. E?-TCL1/p66Shc-/- mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells' level of p66Shc expression. p66Shc expression declined with disease progression in E?-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target.

| S-EPMC6886430 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data