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FIP1L1 (factor interacting with PAPOLA and CPSF1)

Written2014-11Adriana Zámecníkova, Soad Al Bahar
Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait

(Note : for Links provided by Atlas : click)


Other namesFIP1
HGNC (Hugo) FIP1L1
LocusID (NCBI) 81608
Atlas_Id 40577
Location 4q12
Location_base_pair Starts at 54243820 and ends at 54326103 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Fusion genes
(updated 2015)
FIP1L1 (4q12) / PDGFRA (4q12)FIP1L1 (4q12) / RARA (17q21.2)FIP1L1 (4q12) / SBNO2 (19p13.3)
FIP1L1 (4q12) / SORCS1 (10q25.1)
Note Recommended name: Pre-mRNA 3'-end-processing factor FIP1.


Description Belongs to the FIP1 family; predicted to be under the control of a ubiquitous promoter (Gotlib et al., 2004).


Description Contains a region (a 42-amino acid Fip1 motif) of homology to Fip1 (factor interacting with PAP), a yeast protein with synthetic lethal function that is involved in polyadenylation and transcriptional processes; N-terminus contains a PAP-binding site and its C-terminus has an arginine-rich RNA-binding motif (Preker et al., 1995; Kaufmann et al., 2004).
Size: 4 isoforms as a result of splicing processes; the larger transcript has 594 amino acids (molecular weight 66526 Da). In the second isoform (559 amino acids; 63048 Da), exon 9 is deleted. The third isoform is the shortest (378 amino acids; molecular weight 40835 Da) due to the deletion of some exons (exon 2 and 14-18) during splicing processes. In the last isoform, exons 2, 9 and 11 are deleted.
Expression FIP1L1 expression is present in different immunitary cells, embrionic and fetal cells, reproductive tissues, in blood and bone marrow and others.
Localisation Subcellular location: Nucleus.
Function FIP1L1 is an important part of the eukaryotic polyadenylation apparatus that plays a key role in polyadenylation of mRNA precursors (pre-mRNAs) by poly(A) polymerase (PAP). FIP1L1 is an integral component of the cleavage and polyadenylation specificity factor (CPSF) complex that is composed of CPSF1, CPSF2, CPSF3, and FIP1L. This multisubunit complex polyadenylates the 3' end of mRNA precursors by binding to the canonical AAUAAA signal and to U-rich sequences of mRNA precursors. The FIP1L1 protein is an important bridging factor in polyadenylation processes by providing links between RNA, poly(A) polymerase and other multisubunit complexes. Contributes to recognition of polyadenylation signal and may contribute to the differential recognition of various RNAs. It also interacts with poly(A)polymerase (PAP) and CPSF160 forming a ternary complex in vitro, suggesting that they may act together in poly(A) site recognition and in recruitment of PAP to the RNA, thereby stimulating the otherwise weakly active and nonspecific polymerase (Preker et al., 1995). Stimulates poly(A) addition by binding to U-rich elements via arginine-rich RNA binding motif that lies within the C-terminus of the protein, thus significantly contributes to CPSF-mediated stimulation of PAP activity (Kaufmann et al., 2004). FIP1L1 also may act to tether poly(A) polymerase to the CPSF complex and may stabilize the association of PAP with the polyadenylation apparatus. Presumably act as a RNA modulator and active player in transformation from DNA to protein (Preker et al., 1995; Helmling et al., 2001; Kaufmann et al., 2004). Many unknown roles as the exact function of FIP1L1 is unknown.

Implicated in

Entity Various cancers
Note Diseases associated with FIP1L1 include eosinophilia-associated hematological malignancies, juvenile myelomonocytic leukemia (JMML) and acute promyelocytic leukemia ID:1240> (APL). FIP1L1 rearrangements are associated with two distinct leukemogenic fusion genes: FIP1L1-PDGFRA (platelet-derived growth factor receptor alpha) and FIP1L1- (retinoic acid receptor alpha) (Figure 1). Genomic breakpoints in these rearrangements are variable, but FIP1L1 usually breaks within various introns (Vandenberghe et al., 2004; Iwasaki et al., 2014).
Figure 1. Mechanisms of FIP1L1 activation in hematologic malignancies. All known chimeric FIP1L1fusion proteins consists of the amino-terminal amino acids of FIP1L that includes the conserved FIP1 homology domain (40 amino acid Fip1 motif) and the carboxy-terminal part of the partner gene, thus the nuclear localization signal of FIP1L1 is absent in the fusion protein. To date, 2 fusions proteins of FIP1L1 are known: FIP1L1-PDGFRA and FIP1L1-RARA. While FIP1L1-PDGFRA is associated with hematologic disorders with primary eosinophilia, the FIP1L1-RARA fusion was identified in patients with JMML and APL, indicating that FIP1L1 may differentially contribute to the pathogenesis of distinct types of leukemia. In the FIP1L1-PDGFRa fusion protein, the C-terminal PDGFRA portion includes the entire kinase domain but only part of the autoinhibitory juxtamembrane region, making FIP1L1 dispensable for constitutive kinase activation that can be inhibited by administration of tyrosine kinase therapy (imatinib). FIP1 motif in FIP1L1-RARA seems to play a pivotal role in its homodimerization and repression of the retinoic acid response that is required for development of APL (adopted and modified from Gotlib et al., 2004). Abbreviations: N, N-terminal site; C, C-terminal site; TM, transmembrane domain; JM, juxtamembrane domain kinase, kinase domain; DBD, DNA binding domain; LBD, ligand binding domain; JMML, juvenile myelomonocytic leukemia; APL, acute promyelocytic leukemia.
Entity FIP1L1-PDGFRA fusion in eosinophilia-associated hematological malignancies
Note FIP1L1- PDGFRA (platelet-derived growth factor receptor, alpha) fusion have been reported in various neoplasms such as chronic eosinophilic Fusions leukemia, chronic neutrophilic leukemia, systemic mast cell disease, acute myeloid leukemia (AML) and T-cell lymphoblastic lymphoma, - all with overproduction of eosinophils in the blood and bone marrow; may be found in sporadic cases of myeloid sarcoma (granulocytic sarcoma) accompanied by or following AML. (Gotlib et al., 2004; Metzgeroth et al., 2007; Schmitt-Graeff et al., 2014).
Prognosis Excellent with the use of tyrosine kinase inhibitors (imatinib).
Cytogenetics The FIP1L1-PDGFRA fusion gene is the consequence of a cytogenetically invisible interstitial chromosomal deletion of approximately 800 kb on chromosome band 4q12. Occasionally, FIP1L1-PDGFRA fusions are caused by chromosomal translocations such as t(1;4)(q44;q12) and t(4;10)(q12;p11). In both cases, the interstitial deletion creates an in-frame fusion and as a consequence genes between FIP1L1 and PDGFRA are deleted.
Hybrid/Mutated Gene 5'FIP1L1-3'PDGFRA.
Abnormal Protein The encoded FIP1L1-PDGFRA fusion protein consists of the first 233 amino acids of FIP1L1 (including the Fip1 motif) and the C-terminal part of PDGFRA, encompassing the truncated JM region and the entire kinase domain.
Oncogenesis The genomic breakpoints within FIP1L1 have been found to be variably distributed (introns 9-13), whereas all breakpoints in PDGFRA are exclusively found within exon 12, which encompasses the juxtamembrane (JM) domain that is notable for its autoinhibitory function (The interruption of the JM domain of PDGFRA is a consistent feature of FIP1L1-PDGFRA fusions further underlying its functional significance in kinase activation (Walz et al., 2009; Iwasaki et al., 2014)). Similar to the BCR-ABL1 fusion protein in chronic myeloid leukemia, FIP1L1-PDGFRA is a constitutively activated tyrosine kinase that is causally implicated in disease pathogenesis with potential evolution from chronic phase disease to disease progression as well as sensitivity to treatments with tyrosine kinase inhibitors such as imatinib (Cools et al., 2003; Jain et al., 2013).
Entity t(4;17)(q12;q21)/ FIP1L1/RARA
Disease Juvenile myelomonocytic leukemia and acute promyelocytic leukemia.
Prognosis Unknown, as only sporadic cases have been described. Reported cases described similar ATRA response of FIP1L1-RARA to that of PML-RARA fusions.
Cytogenetics t(4;17)(q12;q21).
Hybrid/Mutated Gene In-frame fusion of 5'FIP1L1-3'RARA and 5'RARA-3'FIP1L1.
In all patients the rearrangement fused the RARA exon 3 with exon 15 (Buijs et al., 2007; Kondo et al., 2008) or exon 13 of the FIP1L1 gene (Menezes et al., 2011), in a manner identical to all known RARA associated APL fusions.
Abnormal Protein 832 amino acids; in-frame fusion protein composed of 428 amino-terminal amino acids of FIP1L (including the FIP1 homology domain) and 403 terminal carboxyl-amino acids of RARA, including the DNA and ligand binding domains (Kondo et al., 2008). Alternative splicing of the FIP1L1 portion results in multiple transcript variants similar to FIP1L1-PDGFRA distinct isoforms.
Oncogenesis FIP1L1 is a subunit of the cleavage and polyadenylation specific factor (CPSF) complex that is involved in 3'-end mRNA processing, therefore it is possible that FIP1L1/RARA may interfere with FIP1L1 function (Kaufmann et al., 2004). On the other hand, retinoic acid receptor alpha (RARA), also known as NR1B1 (nuclear receptor subfamily 1, group B, member 1) is a nuclear receptor that is preferentially expressed in myeloid cells. Translocations that involve the RARA gene are characteristic findings in acute promyelocytic leukemia and several RARA partner genes have been identified resulting in various fusion gene products. In all known chimeric RARA fusions the homodimerization ability of fusion proteins appears to be critical for leukemic transformation as well as for repression of retinoic acid-responsive transcriptional activity. While FIP1L1 don't have the known protein-protein interaction domain, experimental studies with deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a role in homodimer formation and transcriptional repressor activity. In fact, homodimer formation was demonstrated in all three identified isoforms of FIP1L1-RARA, as well as RARA-FIP1L1. In addition, FIP1L1-RARA associated with either FIP1L1-RARA or FIP1L1, but not with RARA, further supporting the role of the FIP1L1 portion in homodimerization (Buijs et al., 2007; Kondo et al., 2008; Iwasaki et al., 2014). The FIP1L1 promoter regulated expression may underlie these processes and may influence FIP1L1-RARA-mediated leukemogenesis by differential gene expression of numerous potential target genes and activation of multiple signaling pathways. However, the molecular basis for FIP1L1-RARA- mediated leukemogenesis is most likely complex and still remains to be clarified.


The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase.
Preker PJ, Lingner J, Minvielle-Sebastia L, Keller W.
Cell. 1995 May 5;81(3):379-89.v
PMID 7736590
Fip1 regulates the activity of Poly(A) polymerase through multiple interactions.
Helmling S, Zhelkovsky A, Moore CL.
Mol Cell Biol. 2001 Mar;21(6):2026-37.
PMID 11238938
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG.
N Engl J Med. 2003 Mar 27;348(13):1201-14.
PMID 12660384
The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.
Gotlib J, Cools J, Malone JM 3rd, Schrier SL, Gilliland DG, Coutre SE.
Blood. 2004 Apr 15;103(8):2879-91. Epub 2003 Nov 20. (REVIEW)
PMID 15070659
Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase.
Kaufmann I, Martin G, Friedlein A, Langen H, Keller W.
EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29.
PMID 14749727
Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.
Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D, Herregods MC, Van Hoof A, Selleslag D, Roufosse F, Maerevoet M, Verhoef G, Cools J, Gilliland DG, Hagemeijer A, Marynen P.
Leukemia. 2004 Apr;18(4):734-42.
PMID 14973504
Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia.
Buijs A, Bruin M.
Leukemia. 2007 May;21(5):1104-8. Epub 2007 Feb 15.
PMID 17301809
Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.
Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C, Popp H, Haferlach T, Erben P, Mix J, Muller MC, Beneke H, Muller L, Del Valle F, Aulitzky WE, Wittkowsky G, Schmitz N, Schulte C, Muller-Hermelink K, Hodges E, Whittaker SJ, Diecker F, Dohner H, Schuld P, Hehlmann R, Hochhaus A, Cross NC, Reiter A.
Leukemia. 2007 Jun;21(6):1183-8. Epub 2007 Mar 22.
PMID 17377585
The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia.
Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M.
Haematologica. 2008 Sep;93(9):1414-6. doi: 10.3324/haematol.12854. Epub 2008 Jul 4.
PMID 18603554
The molecular anatomy of the FIP1L1-PDGFRA fusion gene.
Walz C, Score J, Mix J, Cilloni D, Roche-Lestienne C, Yeh RF, Wiemels JL, Ottaviani E, Erben P, Hochhaus A, Baccarani M, Grimwade D, Preudhomme C, Apperley J, Martinelli G, Saglio G, Cross NC, Reiter A; European LeukemiaNet.
Leukemia. 2009 Feb;23(2):271-8. doi: 10.1038/leu.2008.310. Epub 2008 Nov 6.
PMID 18987651
FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia.
Menezes J, Acquadro F, Perez-Pons de la Villa C, Garcia-Sanchez F, Alvarez S, Cigudosa JC.
Haematologica. 2011 Oct;96(10):1565-6. doi: 10.3324/haematol.2011.047134. Epub 2011 Jul 12.
PMID 21750086
Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement.
Jain N, Khoury JD, Pemmaraju N, Kollipara P, Kantarjian H, Verstovsek S.
Blood. 2013 Nov 7;122(19):3387-8. doi: 10.1182/blood-2013-07-516500.
PMID 24203930
FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.
Iwasaki J, Kondo T, Darmanin S, Ibata M, Onozawa M, Hashimoto D, Sakamoto N, Teshima T.
Ann Hematol. 2014 Sep;93(9):1473-81. doi: 10.1007/s00277-014-2085-1. Epub 2014 Apr 25.
PMID 24763514
The FIP1L1-PDGFRA fusion gene and the KIT D816V mutation are coexisting in a small subset of myeloid/lymphoid neoplasms with eosinophilia.
Schmitt-Graeff AH, Erben P, Schwaab J, Vollmer-Kary B, Metzgeroth G, Sotlar K, Horny HP, Kreipe HH, Fisch P, Reiter A.
Blood. 2014 Jan 23;123(4):595-7. doi: 10.1182/blood-2013-10-530642.
PMID 24458279


This paper should be referenced as such :
Zámecníkova A, Al Bahar S
FIP1L1 (factor interacting with PAPOLA and CPSF1);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas)
  del(4)(q12q12) FIP1L1/PDGFRA
t(4;17)(q12;q21) FIP1L1/RARA

External links

HGNC (Hugo)FIP1L1   19124
Entrez_Gene (NCBI)FIP1L1  81608  factor interacting with PAPOLA and CPSF1
GeneCards (Weizmann)FIP1L1
Ensembl hg19 (Hinxton)ENSG00000145216 [Gene_View]  chr4:54243820-54326103 [Contig_View]  FIP1L1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000145216 [Gene_View]  chr4:54243820-54326103 [Contig_View]  FIP1L1 [Vega]
ICGC DataPortalENSG00000145216
TCGA cBioPortalFIP1L1
AceView (NCBI)FIP1L1
Genatlas (Paris)FIP1L1
SOURCE (Princeton)FIP1L1
Genomic and cartography
GoldenPath hg19 (UCSC)FIP1L1  -     chr4:54243820-54326103 +  4q12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)FIP1L1  -     4q12   [Description]    (hg38-Dec_2013)
EnsemblFIP1L1 - 4q12 [CytoView hg19]  FIP1L1 - 4q12 [CytoView hg38]
Mapping of homologs : NCBIFIP1L1 [Mapview hg19]  FIP1L1 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AF161429 AK090938 AK123992 AK295737 AK300398
RefSeq transcript (Entrez)NM_001134937 NM_001134938 NM_030917
RefSeq genomic (Entrez)NC_000004 NC_018915 NG_008644 NT_022853 NW_004929319
Consensus coding sequences : CCDS (NCBI)FIP1L1
Cluster EST : UnigeneHs.624245 [ NCBI ]
CGAP (NCI)Hs.624245
Alternative Splicing : Fast-db (Paris)GSHG0033966
Alternative Splicing GalleryENSG00000145216
Gene ExpressionFIP1L1 [ NCBI-GEO ]     FIP1L1 [ SEEK ]   FIP1L1 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6UN15 (Uniprot)
NextProtQ6UN15  [Medical]  [Publications]
With graphics : InterProQ6UN15
Splice isoforms : SwissVarQ6UN15 (Swissvar)
Domains : Interpro (EBI)Fip1   
Related proteins : CluSTrQ6UN15
Domain families : Pfam (Sanger)Fip1 (PF05182)   
Domain families : Pfam (NCBI)pfam05182   
DMDM Disease mutations81608
Blocks (Seattle)Q6UN15
Human Protein AtlasENSG00000145216
Peptide AtlasQ6UN15
IPIIPI00395337   IPI00008449   IPI00965581   IPI00166352   IPI00658114   IPI00965445   IPI00964076   IPI00968267   
Protein Interaction databases
IntAct (EBI)Q6UN15
Ontologies - Pathways
Ontology : AmiGOprotein binding  nucleoplasm  mRNA cleavage and polyadenylation specificity factor complex  mRNA processing  poly(A) RNA binding  
Ontology : EGO-EBIprotein binding  nucleoplasm  mRNA cleavage and polyadenylation specificity factor complex  mRNA processing  poly(A) RNA binding  
Pathways : KEGGmRNA surveillance pathway   
Protein Interaction DatabaseFIP1L1
Atlas of Cancer Signalling NetworkFIP1L1
Wikipedia pathwaysFIP1L1
Gene fusions - Rearrangements
Fusion : MitelmanFIP1L1/RARA [4q12/17q21.2]  
Fusion : MitelmanFIP1L1/SBNO2 [4q12/19p13.3]  [t(4;19)(q12;p13)]  
Fusion : MitelmanFIP1L1/SORCS1 [4q12/10q25.1]  [t(4;10)(q12;q25)]  
Fusion: TCGAFIP1L1 4q12 SBNO2 19p13.3 BRCA
Fusion: TCGAFIP1L1 4q12 SORCS1 10q25.1 LUAD
Fusion : TICdbFIP1L1 [4q12]  -  PDGFRA [4q12]
Fusion : TICdbFIP1L1 [4q12]  -  RARA [17q21.2]
Polymorphisms : SNP, variants
NCBI Variation ViewerFIP1L1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FIP1L1
Exome Variant ServerFIP1L1
SNP (GeneSNP Utah)FIP1L1
Genetic variants : HAPMAPFIP1L1
Genomic Variants (DGV)FIP1L1 [DGVbeta]
ICGC Data PortalFIP1L1 
TCGA Data PortalFIP1L1 
Tumor PortalFIP1L1
TCGA Copy Number PortalFIP1L1
Cancer Gene: CensusFIP1L1 
Somatic Mutations in Cancer : COSMICFIP1L1 
intOGen PortalFIP1L1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DoCM (Curated mutations)FIP1L1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
DECIPHER (Syndromes)4:54243820-54326103
CONAN: Copy Number AnalysisFIP1L1 
Mutations and Diseases : HGMDFIP1L1
NextProtQ6UN15 [Medical]
Huge Navigator FIP1L1 [HugePedia]  FIP1L1 [HugeCancerGEM]
snp3D : Map Gene to Disease81608
DGIdb (Drug Gene Interaction db)FIP1L1
BioCentury BCIQFIP1L1
General knowledge
Homologs : HomoloGeneFIP1L1
Homology/Alignments : Family Browser (UCSC)FIP1L1
Phylogenetic Trees/Animal Genes : TreeFamFIP1L1
Chemical/Protein Interactions : CTD81608
Chemical/Pharm GKB GenePA134875694
Clinical trialFIP1L1
Cancer Resource (Charite)ENSG00000145216
Other databases
PubMed59 Pubmed reference(s) in Entrez
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

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indexed on : Wed Nov 25 17:37:18 CET 2015

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