Nilotinib Induces Endothelial Cell Dysfunction Independent of ABL1 Inhibition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA954875 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24149346_1.fastq.gz | Fastqsanger.gz | |||
| SRR24149346_2.fastq.gz | Fastqsanger.gz | |||
| SRR24149347_1.fastq.gz | Fastqsanger.gz | |||
| SRR24149347_2.fastq.gz | Fastqsanger.gz | |||
| SRR24149348_1.fastq.gz | Fastqsanger.gz |
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Project description:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor for the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. However, its nephrotoxicity has become prominent with the increase of clinical use, which greatly limits its long-term application. So far, the mechanism of nilotinib’s nephrotoxicity is still unknown leading to a lack of clinical intervention strategies. Here, we found that nilotinib could promote intrinsic apoptosis of both vascular endothelial cells and renal tubular epithelial cells, which was mediated by the excessive ubiquitin-proteasome degradation of anti-apoptotic protein BCL-XL. Moreover, we confirmed that Chloroquine (CQ) could intervene nilotinib-induced apoptosis by reversing the decreased BCL-XL whose mechanism was not relied on autophagy inhibition. Furthermore, RNA-seq analysis was applied to identify the potential target of CQ and the result suggested that CQ could alleviate nilotinib-induced ANKRD1 reduction. Further, we found ANKRD1 abrogated cell apoptosis by preventing ubiquitination of BCL-XL and hence inhibiting BCL-XL degradation. In conclusion, our research reveals the molecular mechanism of nilotinib’s nephrotoxicity, wherein the excessive degradation of BCL-XL via ubiquitin-proteasome pathway promotes kidney cells apoptosis, and provides CQ analogs as the clinical intervention strategy of nilotinib’s nephrotoxicity whose pharmacological effect is dependent on ANKRD1 instead of autophagy inhibition.
2023-09-20 | GSE212122 | GEO
Project description:Nilotinib is a highly effective treatment for chronic myeloid leukemia but has been consistently associated with the development of nilotinib-induced arterial disease (NAD) in a subset of patients. To date, which cell types mediate this effect and whether NAD results from on-target mechanisms is unknown. We utilized human induced pluripotent stem cells (hiPSCs) to generate endothelial cells and vascular smooth muscle cells for in vitro study of NAD. We found that nilotinib adversely affects endothelial proliferation and migration, in addition to increasing intracellular nitric oxide. Nilotinib did not alter endothelial barrier function or lipid uptake. No effect of nilotinib was observed in vascular smooth muscle cells, suggesting that NAD is primarily mediated through endothelial cells. To evaluate whether NAD results from enhanced inhibition of ABL1, we generated multiple ABL1 knockout lines. The effects of nilotinib remained unchanged in the absence of ABL1, suggesting that NAD results from off- rather than on-target signaling. The model established in the present study can be applied to future mechanistic and patient-specific pharmacogenomic studies.
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Project description:BCR::ABL1 drives chronic myeloid leukemia (CML) pathology and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular mechanisms, acting independently of BCR::ABL1, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, drug resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with the SignalingProfiler pipeline, we obtained two signaling maps reporting the BCR::ABL1 dependent and independent pro-survival signalling mechanisms, respectively. Crucial oncogenic pathways were deregulated in resistant cells. To unbiasedly discover therapeutic vulnerabilities, we implemented the Druggability Score, a computational algorithm ranking proteins according to their inferred ability to kill resistant cells when suppressed. By this strategy, we identified a novel and unexpected role for FLT3 in BCR::ABL1 independent resistance. Remarkably, pharmacological suppression of FLT3 triggers death of both resistant cell lines and patients-derived LSCs. Finally, we propose midostaurin treatment as a therapeutic option to improve the clinical outcome of non responder patients and eradicate LSCs.
2025-05-07 | PXD056957 | Pride
Project description:BCR::ABL1 drives chronic myeloid leukemia (CML) disease and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular pathways, acting as BCR::ABL1 independent nechanisms, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, TKI resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with the SignalingProfiler pipeline, we obtained two signaling maps offering a comprehensive description of the BCR::ABL1 dependent and independent pro-survival signalling mechanisms. We leveraged these maps to unbiasedly and systematically discover therapeutic vulnerabilities, by implementing the Druggability Score computational algorithm. By this strategy, and in combination with in vitro and in ex vivo functional assays, we show a crucial role of acquired FLT3-dependency in resistant CML models. In conclusion, we reposition FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for TKI resistant CML patients.
2025-03-31 | GSE280476 | GEO
Project description:Chronic Phase-Chronic Myeloid Leukemia (CP-CML) is defined by the presence of BCR-ABL1 fusione gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signalling pathways which drive the regeneration of LSCs. Despite nilotinib’s action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drives relapse and progression in CML patients. Our study investigated the gene expression profiling (GEP) of BM CD34+/lin- cells from 79 CP-CML patients at diagnosis compared to the BM CD34+/lin- cells from the same patients after 12 months of nilotinib treatment, and to the normal cell counterpart from 10 donors (CTRLs). GEP analyses identified 3012 significantly differentially expressed genes. Among these, we focused on certain genes involved in crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. We demonstrated the upregulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs. We highlighted that certain transcriptome features characterizing the diagnosis persist after 12 months of nilotinib treatment compared to CTRLs, potentially influencing the self-renewal and survival properties of LSCs.
2025-04-02 | GSE279135 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles played by cellular genes in HTLV-1-infected CD4+ T cells await discovery. We combined microarray data and pathway analysis, and found that the ABL1 tyrosine kinase gene is a critical gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes. ABL1 is also part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML), and tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, and dasatinib, are in safe clinical use for treating CML. To evaluate whether ABL1 is indeed critical for the pathogenesis of HAM/TSP, we investigated the effect of ABL1 inhibitors on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and DNA from dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKI. Treating the PBMCs with nilotinib or dasatinib produced significant reductions in the PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, a retrospective survey based on our clinical records found a rare case of HAM/TSP, where the patient also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is a significant gene for the survival of HTLV-1-infected cells and that TKI may be a potential therapeutic agent for HAM/TSP.
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Project description:Purpose: We identified a rare instance of the SFPQ-ABL1 in a child with Ph-like ALL. The overall purpose of this study was to compare the structure and function of the SFPQ-ABL1 fusion to the well characterised BCR-ABL1 fusion. We used phosphoproteomics, transcriptomics and functional assays to determine the transforming capacity, subcellular localisation, and signalling networks of these two fusions. Given the known function of SFPQ in mRNA splicing, transcriptomic analysis was performed to analyse the effect of BCR-ABL1 or SFPQ-ABL1 expression on gene splicing. Methods: mRNA profiles of Ba/F3 cells expressing BCR-ABL1, SFPQ-ABL1, and empty vector control (MSCV) were generated by deep sequencing, in four biologically independent cell lines, using Illumina GAIIx. The sequences were aligned by subread and quantified by featureCounts. Results: In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. We identified no difference in overall splicing between cells expressing BCR-ABL1 and SFPQ-ABL1. Conclusions: SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.
2021-10-15 | GSE185860 | GEO
Project description:Objectives: Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the multifactorial process of TKI-induced vascular adverse effects in a translational model for atherosclerosis, the APOE3*Leiden.CETP mouse. Approach and results: Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed throughout the study, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, :<0.001; ponatinib 3mg/kg, -37%, P<0.001; ponatinib 10 mg/kg -44%, P<0.001) and atherosclerotic lesion area (imatinib, -78%, P<0.001; ponatinib 3 mg/kg, -52%, P=0.014; ponatinib 10 mg/kg, -48%, P=0.001), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis predicted that ponatinib may lead to a pro-coagulant state by adversely affecting coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. The coagulation factor VII in plasma was increased by ponatinib, whereas nilotinib increased FVIIa. Conclusion: Imatinib showed a beneficial cardiovascular risk profile, whereas nilotinib and ponatinib increase the cardiovascular risk through induction of a pro-thrombotic state.
2018-05-24 | GSE103908 | GEO
Project description:BCR-ABL positive acute lymphoblastic leukemia (ALL) cell survival is strongly dependent on the IRE1α-XBP1 branch of the Unfolded Protein Response (UPR). In the study at hand, we have focused on exploring the link between BCR-ABL1 and IRE1α to better understand whether a simultaneous pharmacological inhibition of both pathways could represent a beneficial therapeutic strategy in Philadelphia positive (Ph+) ALL. Therefore, the effect on the phosphoproteome of two inhibitors (MKC-8866 and Nilotinib) as well as a combination of both compounds was analysed in this study.
2020-09-21 | PXD012024 | Pride