A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
BACKGROUND
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.


METHODS
We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.


RESULTS
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.


CONCLUSIONS
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.
Cools
Jan
J
Brigham and Women's Hospital and Harvard Medical School, Boston, USA
DeAngelo
Daniel J
DJ
Gotlib
Jason
J
Stover
Elizabeth H
EH
Legare
Robert D
RD
Cortes
Jorges
J
Kutok
Jeffrey
J
Clark
Jennifer
J
Galinsky
Ilene
I
Griffin
James D
JD
Cross
Nicholas C P
NC
Tefferi
Ayalew
A
Malone
James
J
Alam
Rafeul
R
Schrier
Stanley L
SL
Schmid
Janet
J
Rose
Michal
M
Vandenberghe
Peter
P
Verhoef
Gregor
G
Boogaerts
Marc
M
Wlodarska
Iwona
I
Kantarjian
Hagop
H
Marynen
Peter
P
Coutre
Steven E
SE
Stone
Richard
R
Gilliland
D Gary
DG
D000328:Adult; D001483:Base Sequence; D001549:Benzamides; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy / Q000235:genetics*; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D011995:Recombination, Genetic; D012074:Remission Induction / Q000379:methods
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases