Reference Detail

Ref Type Journal Article
PMID (21224473)
Authors Elling C, Erben P, Walz C, Frickenhaus M, Schemionek M, Stehling M, Serve H, Cross NC, Hochhaus A, Hofmann WK, Berdel WE, Muller-Tidow C, Reiter A, Koschmieder S
Title Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease.
Journal Blood
Vol 117
Issue 10
Date 2011 Mar 10
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
H650Q missense gain of function PDGFRA H650Q lies within the protein kinase domain of the Pdgfra protein (UniProt.org). H650Q results in constitutive activation of Pdgfra, is transforming in culture, and induces leukemia-like disease in animal models (PMID: 21224473).
N659S missense gain of function PDGFRA N659S lies within the protein kinase domain of the Pdgfra protein (UniProt.org). N659S results in constitutive phosphorylation of Pdgfra and Stat5, increased cell proliferation, and is transforming in cell culture (PMID: 21224473).
R748G missense gain of function PDGFRA R748G lies within the protein kinase domain of the Pdgfra protein (UniProt.org). R748G results in constitutive phosphorylation of Pdgfra and Stat5, is transforming in cell culture, and induces leukemia-like disease in animal models (PMID: 21224473).
Y849S missense gain of function PDGFRA Y849S lies within the protein kinase domain of the Pdgfra protein (UniProt.org). Y849S results in constitutive phosphorylation of Pdgfra and Stat5, increased cell proliferation, and is transforming in cell culture (PMID: 21224473).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRA D842_I843delinsIM Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing PDGFRA D842_I843delinsIM were resistant to inhibition of Pdgfra phosphorylation by Gleevec (imatinib) in culture (PMID: 21224473). 21224473
PDGFRA R748G myeloid leukemia sensitive Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gleevec (imatinib) inhibited growth of transformed mouse myeloid cells over expressing PDGFRA R748G in culture and prolonged survival in xenograft models (PMID: 21224473). 21224473
PDGFRA S566_E571delinsR Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation in transformed cells over expressing PDGFRA S566_E571delinsR in culture (PMID: 21224473). 21224473
PDGFRA D846Y Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and cell proliferation in transformed cells over expressing PDGFRA D846Y in culture (PMID: 21224473). 21224473
PDGFRA H845_N848delinsP Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation in transformed cells over expressing PDGFRA H845_N848delinsP in culture (PMID: 21224473). 21224473
JAK2 V617F myeloid leukemia resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed mouse myeloid cells over expressing JAK2 V617F were resistant to Gleevec (imatinib) in culture (PMID: 21224473). 21224473
PDGFRA R841_D842delinsKI Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing PDGFRA R841_D842delinsKI were resistant to inhibition of Pdgfra phosphorylation by Gleevec (imatinib) in culture (PMID: 21224473). 21224473
PDGFRA Y849S Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation and cell proliferation in transformed cells over expressing PDGFRA Y849S in culture (PMID: 21224473). 21224473
PDGFRA V561_I562insER Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited Pdgfra phosphorylation in transformed cells over expressing PDGFRA V561_I562insER in culture (PMID: 21224473). 21224473
PDGFRA N659S myeloid leukemia decreased response Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed mouse myeloid cells over expressing PDGFRA N659S demonstrated reduced sensitivity to Gleevec (imatinib) in culture (PMID: 21224473). 21224473
PDGFRA Y849S myeloid leukemia sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited growth of transformed mouse myeloid cells over expressing PDGFRA Y849S in culture (PMID: 21224473). 21224473
PDGFRA H650Q leukemia sensitive Imatinib Preclinical Actionable In a preclinical study, mice injected with transformed cells harboring PDGFRA H650Q developed leukemia-like disease that is sensitive to Gleevec (imatinib) (PMID: 21224473). 21224473