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: Christian Elling, Philipp Erben, Christoph Walz, Marie Frickenhaus, Mirle Schemionek, Martin Stehling, Hubert Serve, Nicholas C P Cross, Andreas Hochhaus, Wolf-Karsten Hofmann, Wolfgang E Berdel, Carsten Müller-Tidow, Andreas Reiter, Steffen Koschmieder
• Journal: Blood (Blood) Vol. 117 Issue 10 Pg. 2935-43 (Mar 10 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21224473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Blotting, Western
• Cell Separation
• Cell Transformation, Neoplastic (genetics)
• Female
• Flow Cytometry
• Humans
• Hypereosinophilic Syndrome (genetics)
• Imatinib Mesylate
• Leukemia (drug therapy, genetics)
• Male
• Mice
• Piperazines (pharmacology)
• Point Mutation
• Pyrimidines (pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays