Abstract |
Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate ( Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha ( PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe- PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe- PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe- PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.
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Authors | John H Griffin, Joey Leung, Rebecca J Bruner, Michael A Caligiuri, Roger Briesewitz |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 100
Issue 13
Pg. 7830-5
(Jun 24 2003)
ISSN: 0027-8424 [Print] United States |
PMID | 12808148
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Benzamides
- Enzyme Inhibitors
- Indoles
- Peptides
- Phthalazines
- Piperazines
- Pyridines
- Pyrimidines
- Pyrroles
- Recombinant Fusion Proteins
- THRX 165724
- Tyrosine
- vatalanib
- Imatinib Mesylate
- Receptor, Platelet-Derived Growth Factor alpha
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Topics |
- Adult
- Amino Acid Sequence
- Animals
- Antineoplastic Agents
(pharmacology)
- Base Sequence
- Benzamides
- Blotting, Western
- Cell Division
- Cell Line
- Cell Survival
- Cell Transformation, Neoplastic
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Eosinophils
(metabolism)
- Gene Deletion
- Humans
- Hypereosinophilic Syndrome
(blood, drug therapy, enzymology)
- Imatinib Mesylate
- Indoles
(pharmacology)
- Male
- Mice
- Models, Chemical
- Models, Genetic
- Molecular Sequence Data
- Peptides
(chemistry)
- Phthalazines
(pharmacology)
- Piperazines
(pharmacology)
- Precipitin Tests
- Protein Structure, Tertiary
- Pyridines
(pharmacology)
- Pyrimidines
(pharmacology)
- Pyrroles
(pharmacology)
- Receptor, Platelet-Derived Growth Factor alpha
(chemistry)
- Recombinant Fusion Proteins
(genetics, metabolism)
- Recurrence
- Tyrosine
(metabolism)
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