Disease relevance of FIP1L1

• CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy [1].
• A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome [2].
• FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia [3].
• Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia [4].
• Skin biopsy revealed proliferation of CD30+ T cells consistent with lymphomatoid papulosis (LyP), whereas molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene [5].

High impact information on FIP1L1

• CFI(m) is sufficient to direct sequence-specific, A(A/U)UAAA-independent poly(A) addition in vitro through the recruitment of the CPSF subunit hFip1 and poly(A) polymerase to the RNA substrate [6].
• Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12 [7].
• Dysregulated tyrosine kinase activity by the Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) fusion gene has been identified as a cause of clonal hypereosinophilic syndrome (HES), called F/P-positive chronic eosinophilic leukemia (CEL) in humans [8].
• The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease [8].
• We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha) (T674I) mutant [9].

Chemical compound and disease context of FIP1L1

• Myeloproliferative hypereosinophilic syndrome (MHES) is a disorder characterised by male predominance, marked eosinophilia, splenomegaly, tissue fibrosis, elevated serum tryptase and the presence of the FIP1L1/PDGFRA fusion gene in peripheral blood mononuclear cells [10].

Biological context of FIP1L1

• The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months [2].
• Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity [11].
• One patient expressed the FIP1L1-PDGFR-alpha rearrangement gene [12].
• Cytogenetics, FISH and molecular analysis showed the presence of the FIP1L1/PDGFRA fusion gene, recently detected in a majority of HES patients [13].
• DNA sequence analysis demonstrated that the breakpoints of the FIP1L1 and PDGFRalpha genes were present in exon 9 and exon 12, respectively [14].

Anatomical context of FIP1L1

• Deletion of this locus and expression of the FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) for one patient [1].
• One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion [15].
• The bone marrow mast cell infiltration pattern in FIP1L1-PDGFRA(+) SMCD-eos was distinctly diffuse with loose tumoral aggregates [3].
• Rhe irreplaceable image: Superficial thrombosis of a varicose vein of the abdominal wall as the first sign of an otherwise occult locally-advanced ovarian cancer [16].

Associations of FIP1L1 with chemical compounds

• While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not [1].
• In a subset of patients, this is caused by the FIP1L1-PDGFR-alpha fusion tyrosine kinase [17].
• We conclude that AMN107 and imatinib are active and equipotent against cells expressing the FIP1L1-PDGFR-alpha fusion gene [17].
• Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells [17].

Other interactions of FIP1L1

• Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD [1].
• These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES [1].
• Retrospectively, a CHIC2 deletion and the FIP1L1/PDGFRalpha fusion gene-product were demonstrable by FISH analysis and RT-PCR, respectively [18].
• Imatinib is an excellent candidate for first line treatment of Loeffler's endocarditis, especially when the FIP1L1/PDGFA fusion gene is detected [13].
• This case provides further evidence for the potential of co-existence of SM with a primary eosinophilic disorder (CEL) defined by the FIP1L1/PDGFRalpha fusion gene [18].

Analytical, diagnostic and therapeutic context of FIP1L1

• We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion [1].

References