Identification and functional characterization of imatinib‐sensitive DTD1‐PDGFRB and CCDC88C‐PDGFRB fusion genes in eosinophilia‐associated myeloid/lymphoid neoplasms

Eosinophilia-associated myeloid neoplasms with rearrangement of chromosome bands 5q31-33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′-rapid amplification of cDNA ends polymerase chain reaction (5′-RACE-PCR) and DNA-based long-distance inverse PCR (LDI-PCR) with primers derived from PDGFRB. LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′-RACE-PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine-kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled-coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib-sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib.