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FIP1L1 (factor interacting with PAPOLA and CPSF1)

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

Keywords FIP1L1; factor interacting with PAPOLA and CPSF1; cleavage and polyadenylation specificity factor complex; RNA-binding.

(Note : for Links provided by Atlas : click)


Alias (NCBI)FIP1
HGNC (Hugo) FIP1L1
HGNC Alias symbDKFZp586K0717
HGNC Previous nameFIP1 like 1 (S. cerevisiae)
 FIP1L1 cleavage and polyadenylation specific factor subunit
LocusID (NCBI) 81608
Atlas_Id 40577
Location 4q12  [Link to chromosome band 4q12]
Location_base_pair Starts at 53377641 and ends at 53460862 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FIP1L1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CIR1 (2q31.1)::FIP1L1 (4q12)EPB41L1 (20q11.23)::FIP1L1 (4q12)FIP1L1 (4q12)::ASIC2 (17q11.2)
FIP1L1 (4q12)::FIP1L1 (4q12)FIP1L1 (4q12)::PDGFRA (4q12)FIP1L1 (4q12)::RARA (17q21.2)
FIP1L1 (4q12)::SBNO2 (19p13.3)FIP1L1 (4q12)::SORCS1 (10q25.1)PDGFRA (4q12)::FIP1L1 (4q12)
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 (APL). FIP1L1 rearrangements are associated with two distinct leukemogenic fusion genes: FIP1L1- (platelet-derived growth factor receptor alpha) and FIP1L1-RARA (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 / 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.




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
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
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
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
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
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
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
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
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 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
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
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
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


This paper should be referenced as such :
Adriana Zamecnikova, Soad Al Bahar
FIP1L1 (factor interacting with PAPOLA and CPSF1)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(11):650-653.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 9 ]
  del(4)(q12q12) FIP1L1::PDGFRA
ins(9;4)(q33;q12q25) CDK5RAP2::PDGFRA
M3::M3v acute myeloid leukemia (AML M3::M3v)
::Acute promyelocytic leukemia (APL)
::Acute promyelocytic leukemia (APL) PML::RARA

Myeloid::Lymphoid neoplasms with abnormalities of PDGFRA
t(2;4)(p22;q12) STRN::PDGFRA
t(4;10)(q12;p11) KIF5B::PDGFRA
t(4;12)(q12;p13) PDGFRA::ETV6
t(4;17)(q12;q21) FIP1L1::RARA
t(5;17)(q35;q21) NPM1::RARA

External links

HGNC (Hugo)FIP1L1   19124
Entrez_Gene (NCBI)FIP1L1    factor interacting with PAPOLA and CPSF1
AliasesFIP1; Rhe; hFip1
GeneCards (Weizmann)FIP1L1
Ensembl hg19 (Hinxton)ENSG00000145216 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000145216 [Gene_View]  ENSG00000145216 [Sequence]  chr4:53377641-53460862 [Contig_View]  FIP1L1 [Vega]
ICGC DataPortalENSG00000145216
TCGA cBioPortalFIP1L1
AceView (NCBI)FIP1L1
Genatlas (Paris)FIP1L1
SOURCE (Princeton)FIP1L1
Genetics Home Reference (NIH)FIP1L1
Genomic and cartography
GoldenPath hg38 (UCSC)FIP1L1  -     chr4:53377641-53460862 +  4q12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FIP1L1  -     4q12   [Description]    (hg19-Feb_2009)
GoldenPathFIP1L1 - 4q12 [CytoView hg19]  FIP1L1 - 4q12 [CytoView hg38]
Genome Data Viewer NCBIFIP1L1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF161429 AK090938 AK123992 AK295737 AK300398
RefSeq transcript (Entrez)NM_001134937 NM_001134938 NM_001376744 NM_001376745 NM_001376746 NM_001376747 NM_001376748 NM_001376749 NM_001376750 NM_001376751 NM_001376752 NM_001376753 NM_001376754 NM_001376755 NM_001376756 NM_001376757 NM_001376758 NM_001376759 NM_001376760 NM_001376761 NM_001376762 NM_001376764 NM_001376765 NM_001376766 NM_001376767 NM_001376768 NM_001376769 NM_001376770 NM_001376771 NM_001376772 NM_001376773 NM_001376774 NM_001376775 NM_001376776 NM_001376777 NM_001376778 NM_001376779 NM_001376780 NM_001376781 NM_001376782 NM_001376783 NM_001376784 NM_001376785 NM_001376786 NM_030917
Consensus coding sequences : CCDS (NCBI)FIP1L1
Gene ExpressionFIP1L1 [ NCBI-GEO ]   FIP1L1 [ EBI - ARRAY_EXPRESS ]   FIP1L1 [ SEEK ]   FIP1L1 [ MEM ]
Gene Expression Viewer (FireBrowse)FIP1L1 [ Firebrowse - Broad ]
GenevisibleExpression of FIP1L1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)81608
GTEX Portal (Tissue expression)FIP1L1
Human Protein AtlasENSG00000145216-FIP1L1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)FIP1L1
Human Protein Atlas [tissue]ENSG00000145216-FIP1L1 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed111 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:18:06 CEST 2021

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