Distinct Leukemogenic Activity and Imatinib Responsiveness of a BCR-PFGFR Fusion Tyrosine Kinase.
L. Cristina Gavrilescu, PhD1,*,
Nicholas C.P. Cross, PhD2,* and
Richard A. Van Etten, MD, PhD1
1 Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA, USA and 2 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts, United Kingdom.
Chromosomal rearrangements of the platelet-derived growth factorreceptor alpha (PDGFRA) gene on 4q12 have been described ina subset of patients with idiopathic hypereosinophilic syndrome/chroniceosinophilic leukemia (IHES/CEL). The most common, found in1217% of CEL patients, is the FIP1L1-PDGFRA fusion, resultingfrom a cytogenetically invisible deletion on 4q12 (Cools etal., NEJM 2003; 348:1201[Medline]; Griffin et al., PNAS 2003; 100:7830[Abstract/Free Full Text]).FIP1L1-PDGFRA+ CEL patients have an excellent response to low-doseimatinib therapy, often accompanied by complete molecular remission(Pardanani et al., Leuk. Res. 2006; 30:965[Medline]). Additional fusionpartners of PDGFRA include KIF5B and CDK5RAP2 in CEL, and BCRin atypical chronic myeloid leukemia with eosinophilia and t(4;22)(q12;q11)(Baxter et al., Hum. Mol. Genet. 2002; 11:1391[Abstract/Free Full Text]). However, theoncogenic activity and imatinib responsiveness of these otheractivated PDGFRA alleles are unknown. In this study, we assessedthe imatinib sensitivity of BCR-PDGFR and FIP1L1-PDGFR in hematopoieticcell lines, and compared their leukemogenic activity in a mouseretroviral bone marrow transduction/transplantation model. LikeFIP1L1-PDGFR, BCR-PDGFR transformed Ba/F3 cells to become independentof IL-3 for survival and growth. In the absence of IL-3, FIP1L1-PDGFR-expressingBa/F3 cells were 30-fold more sensitive to imatinib than BCR-PDGFR(IC50 = 3 nM vs. 90 nM) for inhibition of proliferation andinduction of apoptosis. A FIP1L1-PDGFR N659D mutant (Cools etal., Cancer Cell 2003; 3:459[Medline]) was relatively resistant to imatinib(IC50 = 200 nM), while the corresponding BCR-PDGFR N659D mutantdisplayed increased imatinib resistance (IC50 > 2 µM).Inhibition of cellular proliferation correlated with decreasedtyrosyl phosphorylation of the respective fusion kinase andof the downstream substrate PLC1. In leukemogenesis experiments,recipients of bone marrow transduced with retrovirus expressingeither FIP1L1-PDGFR or BCR-PDGFR developed fatal myeloproliferativedisease, with similar median and overall survival. This wasaccompanied by significant eosinophilia, relative to the diseaseinduced by BCR-ABL in this model system (Li et al., Blood 2001;97:1442[Abstract/Free Full Text]). Treatment of recipients of FIP1L1-PDGFRA- or BCR-PDGFRA-transducedmarrow with imatinib (125 mg/kg/day by oral gavage for 20 days)suppressed leukocytosis and prolonged their survival. Theseresults suggest that distinct signaling pathways activated byleukemogenic PDGFR fusions in hematopoietic progenitors induceeosinophila in vivo. However, different fusion partners of PDGFRcan significantly influence the sensitivity of the fusion kinaseto imatinib treatment.
* Corresponding author
Disclosure: No relevant conflicts of interest to declare.