Chromosomal rearrangements of the platelet-derived growth factor receptor alpha (PDGFRA) gene on 4q12 have been described in a subset of patients with idiopathic hypereosinophilic syndrome/chronic eosinophilic leukemia (IHES/CEL). The most common, found in 12–17% of CEL patients, is the FIP1L1-PDGFRA fusion, resulting from a cytogenetically invisible deletion on 4q12 (

Cools et al.,
NEJM
2003
;
348
:
1201
;
Griffin et al.,
PNAS
2003
;
100
:
7830
). FIP1L1-PDGFRA+ CEL patients have an excellent response to low-dose imatinib therapy, often accompanied by complete molecular remission (
Pardanani et al.,
Leuk. Res.
2006
;
30
:
965
). Additional fusion partners of PDGFRA include KIF5B and CDK5RAP2 in CEL, and BCR in atypical chronic myeloid leukemia with eosinophilia and t(4;22)(q12;q11) (
Baxter et al.,
Hum. Mol. Genet.
2002
;
11
:
1391
). However, the oncogenic activity and imatinib responsiveness of these other activated PDGFRA alleles are unknown. In this study, we assessed the imatinib sensitivity of BCR-PDGFRα and FIP1L1-PDGFRα in hematopoietic cell lines, and compared their leukemogenic activity in a mouse retroviral bone marrow transduction/transplantation model. Like FIP1L1-PDGFRα, BCR-PDGFRα transformed Ba/F3 cells to become independent of IL-3 for survival and growth. In the absence of IL-3, FIP1L1-PDGFRα-expressing Ba/F3 cells were 30-fold more sensitive to imatinib than BCR-PDGFRα (IC50 = 3 nM vs. 90 nM) for inhibition of proliferation and induction of apoptosis. A FIP1L1-PDGFRα N659D mutant (
Cools et al.,
Cancer Cell
2003
;
3
:
459
) was relatively resistant to imatinib (IC50 = 200 nM), while the corresponding BCR-PDGFRα N659D mutant displayed increased imatinib resistance (IC50 > 2 μM). Inhibition of cellular proliferation correlated with decreased tyrosyl phosphorylation of the respective fusion kinase and of the downstream substrate PLCγ1. In leukemogenesis experiments, recipients of bone marrow transduced with retrovirus expressing either FIP1L1-PDGFRα or BCR-PDGFRα developed fatal myeloproliferative disease, with similar median and overall survival. This was accompanied by significant eosinophilia, relative to the disease induced by BCR-ABL in this model system (
Li et al.,
Blood
2001
;
97
:
1442
). Treatment of recipients of FIP1L1-PDGFRA- or BCR-PDGFRA-transduced marrow with imatinib (125 mg/kg/day by oral gavage for 20 days) suppressed leukocytosis and prolonged their survival. These results suggest that distinct signaling pathways activated by leukemogenic PDGFRα fusions in hematopoietic progenitors induce eosinophila in vivo. However, different fusion partners of PDGFRα can significantly influence the sensitivity of the fusion kinase to imatinib treatment.

Topics:
imatinib mesylate, protein tyrosine kinase, platelet-derived growth factor alpha receptor, mechlorethamine, disseminated eosinophilic collagen disease, eosinophilia, interleukin-3, phosphotransferases, bcr-abl tyrosine kinase, disease remission

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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