Transcriptional activity of a T-ALL PDX line following in vitro treatment with idasanutlin, navitoclax (ABT-263), or combination therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1003809 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25582677_1.fastq.gz | Fastqsanger.gz | |||
| SRR25582677_2.fastq.gz | Fastqsanger.gz | |||
| SRR25582678_1.fastq.gz | Fastqsanger.gz | |||
| SRR25582678_2.fastq.gz | Fastqsanger.gz | |||
| SRR25582679_1.fastq.gz | Fastqsanger.gz |
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Project description:Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating senescent cells in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 (Navitoclax) and a DMSO control directly to the skin of 24-month-old mice over a 5-day period. Following ABT-263 treatment, aged skin showed decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to the DMSO-treated skin. However, ABT-263 treatment also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice treated with ABT-263 exhibited accelerated wound closure compared to the DMSO control group. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis and the resulting inflammation, which in turn stimulated the expression of genes involved in extracellular matrix remodeling and wound repair pathways.
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Project description:To explore the role played by senescent cells in mice models of pulmonary hypertension we exposed young C57BL6/j mice to 8 days hypoxia or normoxia and treated with senolytic drug ABT-263 (50mg/kg/day) or its vehicule. We then performed lung gene expression profiling analysis using data obtained from RNA-seq of 4 groups of mice (Normoxia+Vehicule; Normoxia+ABT-263; Hypoxia+Vehicule; Hypoxia+ABT-263)
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Project description:Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing
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Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Experiment Overall Design: Naive cell lines were isolated in duplicate or triplicate (only a single for H69AR) to determine RNA expression pattern.
2008-06-19 | E-GEOD-10841 | biostudies-arrayexpress
Project description:Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.
2024-08-15 | GSE240805 | GEO
Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Keywords: cell line comparison
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