title: Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease.
abstract: The FIP1L1-PDGFRA fusion is seen in a fraction of cases with a presumptive diagnosis of hypereosinophilic syndrome (HES). However, because most HES patients lack FIP1L1-PDGFRA, we studied whether they harbor activating mutations of the PDGFRA gene. Sequencing of 87 FIP1L1-PDGFRA-negative HES patients revealed several novel PDGFRA point mutations (R481G, L507P, I562M, H570R, H650Q, N659S, L705P, R748G, and Y849S). When cloned into 32D cells, N659S and Y849S and-on selection for high expressors-also H650Q and R748G mutants induced growth factor-independent proliferation, clonogenic growth, and constitutive phosphorylation of PDGFRA and Stat5. Imatinib antagonized Stat5 phosphorylation. Mutations involving positions 659 and 849 had been shown previously to possess transforming potential in gastrointestinal stromal tumors. Because H650Q and R748G mutants possessed only weak transforming activity, we injected 32D cells harboring these mutants or FIP1L1-PDGFRA into mice and found that they induced a leukemia-like disease. Oral imatinib treatment significantly decreased leukemic growth in vivo and prolonged survival. In conclusion, our data provide evidence that imatinib-sensitive PDGFRA point mutations play an important role in the pathogenesis of HES and we propose that more research should be performed to further define the frequency and treatment response of PDGFRA mutations in FIP1L1-PDGFRA-negative HES patients.
authors.affiliation: Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Elling
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.forename: Marie
authors.initials: M
authors.lastname: Frickenhaus
authors.forename: Mirle
authors.initials: M
authors.lastname: Schemionek
authors.forename: Martin
authors.initials: M
authors.lastname: Stehling
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics*; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha