- OMIM ID: 607686
- OMIM diseaseName:
- OMIM diseaseClinical_Synopsis:
- OMIM diseaseText:
In an analysis of DNA from a patient with idiopathic hypereosinophilic
syndrome (HES; 607685) in whom a complex chromosomal rearrangement had
been identified, Cools et al. (2003) identified an interstitial deletion
on chromosome 4q12 that resulted in fusion of the platelet-derived
growth factor receptor-alpha gene (PDGFRA; 173490) to a gene encoding a
putative 520-amino acid protein that most closely resembled Fip1, an
essential component of the polyadenylation machinery of S. cerevisiae
(Preker et al., 1995). Cools et al. (2003) therefore designated the gene
Fip1-like-1 (FIP1L1). Data derived from EST database searches indicated
that FIP1L1 is widely expressed and undergoes alternative splicing.
Griffin et al. (2003) also found the 4q12 deletion in patients with HES,
resulting in the same fusion gene involving PDGFRA and FIP1L1. They
suggested that FIP1L1 be referred to as RAG (rearranged in
- FIP1L1-PDGFRA Fusion Protein
Cools et al. (2003) determined that the FIP1L1-PDGFRA fusion gene
encodes a constitutively activated tyrosine kinase that transforms
hematopoietic cells and is inhibited by imatinib. The FIP1L1-PDGFRA
fusion gene is in-frame and fuses the first 233 amino acids of FIP1L1 to
the last 523 amino acids of PDGFRA.
Griffin et al. (2003) demonstrated that the FIP1L1-PDGFRA fusion kinase
is constitutively phosphorylated and supports IL3-independent growth
when expressed in BaF3 cells. Proliferation and viability of EOL-1 and
BaF3 cells expressing the fusion protein were ablated by imatinib and 2
other inhibitors of PDGFRA.
Stover et al. (2006) stated that several variations of the FIP1L1/PDGFRA
fusion protein have been identified in clinical studies of HES and
systemic mast cell disease, but in all disease-associated cases, the
autoinhibitory juxtamembrane (JM) domain of PDGFRA has been disrupted.
By examining the kinase activity of several FIP1L1/PDGFRA fusion
proteins, they determined that the FIP1L1 sequence was completely
dispensable for PDGFRA activation in vitro and in vivo. On the other
hand, N-terminal truncation of PDGFRA between 2 conserved tryptophan
residues in the JM region was required for kinase activation and
transforming potential of FIP1L1/PDGFRA. The presence of a complete JM
domain in the FIP1L1/PDGFRA fusion protein inhibited activation of
PDGFRA kinase activity.
The FIP1L1 gene maps to chromosome 4q12 (Cools et al., 2003; Griffin et
Cools et al. (2003) and Griffin et al. (2003) identified an interstitial
deletion on chromosome 4q12 in patients with HES that resulted in fusion
of the FIP1L1 gene with exon 12 of the PDGFRA gene.
- OMIM diseaseSee_Also:
- OMIM diseaseAllelic_Variants:
- OMIM diseaseCreation_Date: Victor A. McKusick: 4/10/2003
- OMIM diseaseEdit_History_Data: mgross: 07/07/2006
- OMIM diseaseContributors: Patricia A. Hartz - updated: 7/6/2006
Victor A. McKusick - updated: 7/23/2003
- OMIM diseaseReference: 1. Cools, J.; DeAngelo, D. J.; Gotlib, J.; Stover, E. H.; Legare,
R. D.; Cortes, J.; Kutok, J.; Clark, J.; Galinsky, I.; Griffin, J.
D.; Cross, N. C. P.; Tefferi, A.; and 14 others: A tyrosine kinase
created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic
target of imatinib in idiopathic hypereosinophilic syndrome. New
Eng. J. Med. 348: 1201-1214, 2003.
2. Griffin, J. H.; Leung, J.; Bruner, R. J.; Caligiuri, M. A.; Briesewitz,
R.: Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic
syndrome. Proc. Nat. Acad. Sci. 100: 7830-7835, 2003.
3. Preker, P. J.; Lingner, J.; Minvielle-Sebastia, L.; Keller, W.
: The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation
factor that directly interacts with poly(A) polymerase. Cell 81:
4. Stover, E. H.; Chen, J.; Folens, C.; Lee, B. H.; Mentens, N.; Marynen,
P.; Williams, I. R.; Gilliland, D. G.; Cools, J.: Activation of FIP1L1-PDGFR-alpha
requires disruption of the juxtamembrane protein of PDGFR-alpha and
is FIP1L1-independent. Proc. Nat. Acad. Sci. 103: 8078-8083, 2006.