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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). |
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| 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. |
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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). |
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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. |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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