ArticleLeukemia2015
F604S exchange in FIP1L1-PDGFRA enhances FIP1L1-PDGFRA protein stability via SHP-2 and SRC: a novel mode of kinase inhibitor resistance.
Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 12 citations in OpenAlex.
- S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells.Frontiers in immunology · 2020Article
- SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells.Medical science monitor : international medical journal of experimental and clinical research · 2017Article
- Article
- Platelet-derived growth factor (PDGF) signalling in cancer: rapidly emerging signalling landscape.Cell biochemistry and function · 2015Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FIP1L1-PDGFRA is a constitutively activated kinase described in chronic eosinophilic leukemia (CEL) and hypereosinophilic syndrome (HES). Imatinib is clinically active in FIP1L1-PDGFRA-positive diseases. Using in vitro screening to identify imatinib-resistant mutations, we frequently detected a Phe to Ser exchange at position 604 (F604S) of FIP1L1-PDGFRA alone or in combination with other exchanges. Surprisingly, FIP1L1-PDGFRA/F604S did not increase the biochemical or cellular IC50 value of imatinib when compared with unmutated FIP1L1-PDGFRA. However, FIP1L1-PDGFRA/F604S more efficiently induced growth factor independence in cell lines and primary mouse bone marrow cells. Pulse chase analysis revealed that the F604S exchange strongly stabilized FIP1L1-PDGFRA/F604S. The F604S mutation creates a binding site for the phosphatase domain of SHP-2, leading to lower autophosphorylation of FIP1L1-PDGFRA/F604S. This is associated with a reduced activation of SRC and CBL by FIP1L1-PDGFRA/F604S compared with the unmutated oncogene. As SRC inhibition and knockdown resulted in FIP1L1-PDGFRA stabilization, this explains the extended half-life of FIP1L1-PDGFRA/F604S. Interestingly, FIP1L1-PDGFRA/L629P, a recently identified mutation in an imatinib-resistant CEL patient, also showed protein stabilization similar to that observed with FIP1L1-PDGFRA/F604S. Therefore, resistance mutations in FIP1L1-PDGFRA that do not interfere with drug binding but rather increase target protein stability seem to be one of the drug-resistance mechanisms in FIP1L1-PDGFRA-positive disease.
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