FIP1 like 1–platelet-derived growth factor receptor alpha fusion protein (FIP1L1-PDGFRA)

The FIP1L1-PDGFRA fusion protein is an oncogenic fusion kinase created by an 800 kb interstitial deletion on chromosome 4q12, fusing the 5’ region of the FIP1L1 gene (which encodes a component of the cleavage and polyadenylation specificity factor complex) to the 3’ region of the PDGFRA gene (which encodes the platelet-derived growth factor receptor alpha, a receptor tyrosine kinase)[1][3][5][6]. This fusion results in loss of the auto-inhibitory juxtamembrane domain of PDGFRA, causing the tyrosine kinase domain to become constitutively active[1][2]. The aberrant kinase signaling leads to uncontrolled proliferation and differentiation of myeloid lineage cells, often resulting in diseases such as hypereosinophilic syndrome, chronic eosinophilic leukemia, myeloid and lymphoid neoplasms with eosinophilia, and occasionally acute leukemias[1][2][5]. FIP1L1-PDGFRA is highly sensitive to the kinase inhibitor imatinib, which can induce rapid and durable clinical responses; however, resistance-conferring mutations (notably T674I) can arise[5]. The presence of this fusion gene is an established diagnostic and therapeutic biomarker in relevant hematologic malignancies, and its detection guides the use of targeted therapy[2][5].

Other names

FIP1L1-PDGFRα fusion proteinFIP1L1::PDGFRAFIP1L1–PDGFRA

Inhibition of constitutive tyrosine kinase activity (blockade of ATP-binding on kinase domain)