The Platelet-Derived Growth Factor Receptor beta Fuses to Two Distinct Loci at 3p21 in Imatinib Responsive Chronic Eosinophilic Leukemia.

We have identified three patients (2 adults, one infant) who presented with BCR-ABL negative eosinophilic myeloproliferative disorders. Cytogenetic analysis revealed a t(1;3;5)(p36;p21;q33) for case 1 and a t(3;5)(p21–25;q31–35) for cases 2 and 3. Two-color fluorescence in situ hybridization (FISH) using differentially labelled probes flanking PDGFRB indicated that this gene was disrupted in all three cases. 5′ rapid amplification of cDNA ends (5′RACE) for case 1 identified an in-frame mRNA fusion of exon 9 of the WDR48 gene at 3p21 to exon 12 of PDGFRB. The chimeric mRNA is predicted to encode a 872 amino acid fusion protein that retains the amino terminal WD repeat region of WDR48 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Cases 2 and 3 were negative for the WDR48-PDGFRB fusion mRNA by RT-PCR using several combinations of primers. 5′RACE PCR from case 2 RNA identified a fusion involving a second 3p21 gene: GOLGA4 exon 11 was fused in-frame to exon 11 of PDGFRB. Exactly the same fusion was found in case 3. The predicted 991 amino acid protein included the amino terminal coiled-coil domain of GOLGA4 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Interestingly, both WDR48 and GOLGA4 are involved in endocytic shuttling pathways. The presence of all fusions was confirmed by RT-PCR and identification of the genomic breakpoints. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of patient CFU-GM for case 2. Following the identification of PDGFRB rearrangements, all three patients were treated with imatinib. Case 1 was in transformation, but responded rapidly to minimal doses of imatinib (800mg daily for 4 days) with complete cytogenetic remission but remained pancytopenic. Blast crisis recurred 8 months later, responded similarly to 3 days of imatinib, but the patient died 2 months later of invasive fungal infection. Case 2 responded clinically and remains in sustained cytogenetic and molecular remission (nested RT-PCR negative for GOLGA4-PDGFRB). Case 3 (a 13 month old boy) had a complete hematologic response to 50mg/day imatinib but the t(3;5) was still seen in 40% of metaphases at 3 months. We conclude that PDGFRB fuses to diverse partner genes to give rise to atypical MPDs. Although very rare, identification of these fusions is critical for proper management of affected individuals.