Retrospective RNA Sequencing Reclassifies a Historical t(5;12) Eosinophilic Neoplasm From Presumed PDGFRB Rearrangement to ETV6::ACSL6

Abstract

The molecular interpretation of eosinophilic neoplasms harboring t(5;12) may be challenging because cytogenetic breakpoint assignments can suggest a PDGFRB rearrangement without identifying the underlying fusion. We retrospectively investigated a woman with a chronic eosinophilic myeloid neoplasm initially investigated in 2002, in whom a subsequent t(5;12)(q31 ~ q33;p13) raised suspicion of PDGFRB involvement. Contemporary molecular investigations failed to identify the rearrangement, and an empiric trial of imatinib produced no meaningful hematologic response. Seventeen years later, blast transformation was accompanied by persistence of t(5;12) and acquisition of del(9)(q22). Fluorescence in situ hybridization demonstrated ETV6 rearrangement but no PDGFRB break-apart pattern, indicating en bloc translocation of the PDGFRB locus. Targeted RNA sequencing of archived RNA extracted from cryopreserved peripheral blood cells collected in 2004 subsequently identified a strong-evidence ETV6::ACSL6 fusion joining exon 2 of ETV6 to exon 2 of ACSL6, supported by 1847 reads and 218 unique start sites. Targeted myeloid DNA sequencing detected no mutation within the regions analyzed. Identification of ETV6::ACSL6 shifted the biological interpretation away from presumed constitutive tyrosine kinase activation toward a proposed cytokine regulatory rewiring involving the 5q31 cytokine locus, consistent with published experimental evidence and the absence of response to imatinib. This case illustrates how contemporary RNA-based fusion detection can resolve a historically uncharacterized structural rearrangement and refine biological interpretation and therapeutic expectations, while documenting an unusually prolonged natural history of an ETV6::ACSL6-associated eosinophilic myeloid neoplasm.