Transient Response to Imatinib in an Atypical Chronic Myeloproliferative Disease Associated with ins(9;4)(q34;q21q31) and a CDK5RAP2-PDGFRA Fusion Gene.

Chronic myeloproliferative disorders (CMPD) associated with rearrangements of the ‘platelet-derived growth factor receptor A’ (PDGFRA) at chromosome 4q12 are excellent candidates for targeted therapy with imatinib. To date, two fusion genes involving PDGFRA have been described: FIP1L1-PDGFRA and BCR-PDGFRA. Here we report a female patient who presented in advanced phase of an atypical myeloproliferative disease. Routine cytogenetic analysis revealed an ins(9;4)(q34;q21q31). Although no break was visible at 4q12, FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. To identify the partner gene we employed 5′-RACE PCR, exploiting the fact that all known PDGFRA fusions involve exon 12 of this gene. The resulting PCR-products consisted of 5′-sequences derived from CDK5RAP2 (CDK5 regulatory subunit associated protein 2) located on 9q33 and 3′-sequences derived from PDGFRA. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. FISH analysis confirmed the co-localization of 5′ CDK5RAP2 and 3′ PDGFRA sequences. RT-PCR confirmed the in-frame mRNA fusion between exon 13 of CDK5RAP2, a 40-bp insert which was partially derived from PDGFRA intron 11 and a truncated PDGFRA exon 12. No reciprocal fusion transcript could be amplified by RT-PCR. The predicted CDK5RAP2-PDGFRA protein consists of 1003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerisation domains of CDK5RAP2 suggesting a mechanism of tyrosine kinase activation similar to BCR-ABL. Treatment with 400 mg imatinib was initiated and the patient achieved a complete cytogenetic and molecular remission. However, hematological response was only partial with residual blasts repeatedly detectable in the blood and marrow. The patient rapidly developed acute leukemia while still remaining in complete cytogenetic and molecular remission suggesting the outgrowth of a second imatinib-resistant leukemic clone. These findings and the fact that the ins(9;4) was only seen in 24% of metaphases at diagnosis suggests that CDK5RAP2-PDGFRA may have been a secondary abnormality. In summary, we have identified a third fusion gene involving PDGFRA, underlining the fundamental role of activated tyrosine kinases in CMPD’s and their possible response to targeted therapy with imatinib.