FIP1-like 1-platelet-derived growth factor receptor alpha fusion kinase (FIP1L1-PDGFRα) (FIP1L1-PDGFRα)

The FIP1L1-PDGFRα fusion kinase is a constitutively active tyrosine kinase resulting from an interstitial deletion on chromosome 4q12, which fuses the FIP1L1 gene to the PDGFRA gene [1.2.3, 1.3.2]. This genetic rearrangement disrupts the autoinhibitory juxtamembrane domain of the platelet-derived growth factor receptor alpha (PDGFRα), leading to ligand-independent signaling and uncontrolled cellular growth [1.1.2, 1.3.5]. The fusion protein primarily drives the pathogenesis of FIP1L1-PDGFRα-positive chronic eosinophilic leukemia (CEL) and a subset of hypereosinophilic syndromes (HES) by activating downstream pathways such as STAT5, PI3K/Akt, and MAPK [1.3.3, 1.3.5]. It is a highly sensitive target for the tyrosine kinase inhibitor imatinib, which typically induces rapid and durable hematologic and molecular remissions [1.1.1, 1.4.3]. However, the emergence of resistance mutations, particularly the T674I gatekeeper mutation, presents a significant therapeutic challenge, often requiring treatment with next-generation inhibitors like ponatinib [1.4.1, 1.4.2]. Monitoring for the FIP1L1-PDGFRA fusion gene via RT-PCR or FISH is essential for diagnosis and for tracking minimal residual disease during therapy [1.1.1, 1.1.2].

Other names

FIP1L1-PDGFRAFIP1L1/PDGFRA fusion proteinF/P fusion kinasedel(4)(q12) fusion proteinFIP1L1-PDGFR alpha

Tyrosine kinase inhibition via competitive binding to the ATP-binding site of the PDGFRα kinase domain.