Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.
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.
Griffin
John H
JH
Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA.
Leung
Joey
J
Bruner
Rebecca J
RJ
Caligiuri
Michael A
MA
Briesewitz
Roger
R
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001549:Benzamides; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007211:Indoles; D010455:Peptides; D010793:Phthalazines; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; C475928:THRX 165724; D014443:Tyrosine; C404768:vatalanib; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha