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Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically-heterogeneous mouse model of T-cell acute lymphoblastic leukemia

ABSTRACT: Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically-heterogeneous mouse model of T-cell acute lymphoblastic leukemia

PROVIDER: PRJNA564781 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10082655_1.fastq.gz	Fastqsanger.gz
	SRR10082655_2.fastq.gz	Fastqsanger.gz
	SRR10082656_1.fastq.gz	Fastqsanger.gz
	SRR10082656_2.fastq.gz	Fastqsanger.gz
	SRR10092556_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically heterogeneous mouse model of T-cell acute lymphoblastic leukemia.

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer derived from the malignant transformation of T-cell progenitors. Outcomes remain poor for T-ALL patients who have either primary resistance to standard-of-care chemotherapy or disease relapse. Notably, there are currently no targeted therapies available in T-ALL. This lack of next-generation therapies highlights the need for relevant preclinical disease modeling to identify and validate new targets and treatment approaches. Here, we adapted a spontaneously arising, genetically heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies. Genetic engineering of the murine Notch1 locus aligned the spectrum of Notch1 mutations in the mouse model to that of human T-ALL and confirmed aberrant, recombination-activating gene (RAG)-mediated 5' Notch1 recombination events as the preferred pathway in murine T-ALL development. Testing of Notch1-targeting therapeutic antibodies demonstrated T-ALL sensitivity to different classes of Notch1 blockers based on Notch1 mutational status. In contrast, genetic ablation of Notch3 did not impact T-ALL development. The T-ALL model was further applied to the testing of immunotherapeutic agents in fully immunocompetent, syngeneic mice. In line with recent clinical experience in T-cell malignancies, programmed cell death 1 (PD-1) blockade alone lacked anti-tumor activity against murine T-ALL tumors. Overall, the unique features of the spontaneous T-ALL model coupled with genetic manipulations and the application to therapeutic testing in immunocompetent backgrounds will be of great utility for the preclinical evaluation of novel therapies against T-ALL.

| S-EPMC6765191 | biostudies-literature

Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically-heterogeneous mouse model of T-cell acute lymphoblastic leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-09-10 | GSE137181 | GEO

Exome sequencing of thymus transplantation based spontaneous murine T cell acute lymphoblastic leukemia (T-ALL) model

Project description:We adapted a spontaneously-arising, genetically-heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies.

2019-09-10 | GSE137179 | GEO

Gene expression profile of thymus transplantation based spontaneous murine T cell acute lymphoblastic leukemia (T-ALL) model

2019-09-07 | GSE137057 | GEO

Pre-clinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

Project description:Multiple myeloma (MM) is a neoplasia of bone marrow (BM) plasma cells that remains largely incurable with current treatment. Advancing therapeutic discoveries has been hampered by the lack of genetically heterogeneous models of MM. To circumvent this limitation, we engineered fifteen mouse models carrying combinations of eight MM genetic drivers, which fulfilled the pathogenesis of human disease including progression from premalignant states under immune surveillance. Integrative analyses of ⁓500 mice and ⁓1,000 patients revealed a MAPK-MYC genetic pathway that regulates time to progression and immune escape mechanisms across genetically heterogeneous tumors. During progression, MYC-dependent and independent remodeling of the BM microenvironment divided MM into immune categories with predominance of selected T-cell subpopulations, which dictated immunotherapy responses. Experimental targeting of the cytotoxic or immunosuppressive T-cell states observed in refractory MM patients enhanced immunotherapy effectiveness. Our resource enabled characterization of MM cell-intrinsic and immunological traits at unprecedented levels, which will accelerate the translation of personalized immunotherapy.

2023-01-31 | GSE220997 | GEO

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

Project description:Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of Phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PIK3/Akt signaling which regulates the spliceosome and cell cycle machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.

2024-01-26 | PXD038908 | Pride

Notch

Project description:Notch

| PRJNA988118 | ENA

NOTCH signaling in T-cell acute lymphoblastic leukemia cell lines

Project description:In T-cell acute lymphoblastic leukemia (T-ALL) NOTCH 1 receptors are frequently mutated. This leads to aberrantly high Notch signaling, but how this translates into deregulated cell cycle control and the transformed cell type is poorly understood. In this report, we analyze downstream responses resulting from the high level of NOTCH 1 signaling in T-ALL. Notch activity, measured immediately downstream of the NOTCH 1 receptor, is high, but expression of the canonical downstream Notch response genes HES 1 and HEY 2 is low both in primary cells from T-ALL patients and in T-ALL cell lines. This suggests that other immediate Notch downstream genes are activated, and we found that Notch signaling controls the levels of expression of the E3 ubiquitin ligase SKP2 and its target protein p27Kip1. We show that in T-ALL cell lines, recruitment of NOTCH 1 ICD to the SKP2 promoter was accompanied by high SKP2 and low p27Kip1 protein levels were low. In contrast, pharmacologically blocking Notch signaling reversed this picture and led to loss of NOTCH 1 ICD occupancy of the SKP2 promoter, decreased SKP2 and increased p27Kip1 expression. T-ALL cells show a rapid G1-S cell cycle transition, while blocked Notch signaling resulted in G0/G1 cell cycle arrest, also observed by transfection of p27Kip1 or, to a smaller extent, a dominant negative SKP2 allele. Collectively, our data suggest that the aberrantly high Notch signaling in T-ALL maintains SKP2 at a high level and reduces p27Kip1, which leads to more rapid cell cycle progression. Keywords: comparative genomic hybridization

2006-12-15 | GSE6495 | GEO

Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

Project description:NOTCH1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to toxicity and development of resistance, thus restricting their clinical efficacy. Here we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta (PKCδ). We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance “in-vitro”. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

2021-03-08 | PXD018744 | Pride

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

2022-10-13 | PXD034938 | Pride

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