ArticleProceedings of the National Academy of Sciences of the United States of America2012
Imatinib resistance and microcytic erythrocytosis in a KitV558Δ;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells.Protein & cell · 2024Article
- Modeling human gastric cancers in immunocompetent mice.Cancer biology & medicine · 2024Review
- Regorafenib-related erythrocytosis in metastatic extra-gastrointestinal stromal tumor: a case report.Frontiers in oncology · 2024Article
- Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.Molecular cancer · 2023Review
- New C3H KitScientific reports · 2022Article
- Monitoring longitudinal disease progression in a novel murine Kit tumor model using high-field MRI.Scientific reports · 2022Article
- Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST.Cancer immunology research · 2021Article
- Role ofFrontiers in cell and developmental biology · 2021Review
- The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.Oncogene · 2020Article
- Stem cell factor: the bridge between bone marrow adipocytes and hematopoietic cells.Haematologica · 2019Article
- Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity.The Journal of experimental medicine · 2019Article
- Macrophages and CD8Cancer immunology research · 2018Article
- Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- ETV1-Positive Cells Give Rise toCancer research · 2017Article
- Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.Oncogene · 2017Article
- The spleen microenvironment influences disease transformation in a mouse model of KITScientific reports · 2017Article
- Article
- High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias.The Journal of experimental medicine · 2014Article
- KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion.Stem cells (Dayton, Ohio) · 2013Article
- Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket.PloS one · 2013Article
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
Most gastrointestinal stromal tumors (GISTs) harbor a gain-of-function mutation in the Kit receptor. GIST patients treated with the tyrosine kinase inhibitor imatinib frequently develop imatinib resistance as a result of second-site Kit mutations. To investigate the consequences of second-site Kit mutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit(V558Δ) mutation found in a familial case of GIST and the Kit(T669I) (human KIT(T670I)) "gatekeeper" mutation found in imatinib-resistant GIST patients. Similar to Kit(V558/+) mice, Kit(V558;T669I/+) mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit(V558/+) control mice, treatment of the Kit(V558;T669I/+) mice with either imatinib or dasatinib failed to inhibit oncogenic Kit signaling and GIST growth. However, this resistance could be overcome by treatment of Kit(V558;T669I/+) mice with sunitinib or sorafenib. Although tumor lesions were smaller in Kit(V558;T669I/+) mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in Kit(V558;T669I/+) mice. Strikingly, the Kit(V558;T669I/+) mice developed a pronounced polycythemia vera-like erythrocytosis in conjunction with microcytosis. This mouse model should be useful for preclinical studies of drug candidates designed to overcome imatinib resistance in GIST and to investigate the consequences of oncogenic KIT signaling in hematopoietic as well as other cell lineages.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.