A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome

Brigham and Women's Hospital and Harvard Medical School, Boston, USA
New England Journal of Medicine (Impact Factor: 55.87). 04/2003; 348(13):1201-14. DOI: 10.1056/NEJMoa025217
Source: PubMed


Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.
We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.
Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). 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. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.
The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

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    • "It was recently suggested that MPN-eo with rearrangement of " januskinase 2 " (JAK2) should also be included in this category (Patterer et al., 2013; Bain and Ahmad, 2014). The most common MPN-eo-associated individual TK fusion genes are FIP1L1-PDGFRA, ETV6-PDGFRB, ZNF198-FGFR1, and PCM1-JAK2 (Golub et al., 1994; Xiao et al., 1998; Cools et al., 2003; Reiter et al., 2005). "
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    ABSTRACT: In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5'-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 09/2015; 54(12). DOI:10.1002/gcc.22287 · 4.04 Impact Factor
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    • "stance to TKIs targeting breakpoint cluster region - abelson tyrosine kinase ( BCR - ABL ) fusion in chronic myelogenous leukaemia ( Gorre et al . , 2001 ; Shah et al . , 2002 ) , EGFR in nonsmall cell lung cancer ( Kobayashi et al . , 2005 ; Pao et al . , 2005 ) , platelet - derived growth factor receptor ( PDGFR ) in hypereosinophilic syndrome ( Cools et al . , 2003 ) , KIT in gastrointestinal stromal tumours ( Tamborini et al . , 2006 ) and echinoderm microtubule - associated protein - like 4 - anaplastic lymphoma kinase ( EML4 - ALK ) fusion in lung cancer ( Choi et al . , 2010b ) . Modelling in cell culture has also been suc - cessfully used to discover clinically relevant acquired resistance an"
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    02/2015; 19(3). DOI:10.1016/j.ebiom.2015.02.009
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    • "HES patients with a FIP1L1-PDGFRA rearrangement are now reclassified as chronic eosinophilic leukemia (CEL), as this gene has become a marker of disease clonality [60]. This fusion gene leads to constitutive activation of the PDGFRA TK [61]. Asymptomatic HES patients lacking evidence of organ damage are closely monitored, although there is no general consensus on how to treat them. "
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