Myeloid Neoplasms With a t(5;12)(q31;p13) and an Associated ETV6::ACSL6 Gene Fusion Are Diagnostically Challenging...

The ETV6::ACSL6 fusion gene resulting from the reciprocal translocation t(5;12)(q31;p13) is a rare but recurrent aberration in patients with myeloid neoplasms of variable phenotype. Cytogenetically, there is a high resemblance to the t(5;12)(q32;p13) leading to the imatinib-sensitive ETV6::PDGFRB fusion gene. Therefore, distinction of these entities by complementary molecular genetic tools is crucial, as patients with ETV6::ACSL6 fusion have a poor prognosis with no response to imatinib or alternative tyrosine kinase inhibitors (TKI). We performed a comprehensive analysis of 7 patients harboring the ETV6::ACSL6 fusion, using clinical and morphological characteristics, chromosome banding analysis (CBA), fluorescence in situ hybridization (FISH) and molecular genetic analyses including whole transcriptome sequencing (WTS) as well as whole genome sequencing (WGS). Patients presented with an increase in leukocytes, eosinophils and basophils. The phenotype was a chronic myeloid neoplasm in 6 patients and acute myeloid leukemia (AML) in 1 patient. The t(5;12)(q31;p13) was the sole abnormality in four out of seven cases, and the remaining 3 cases showed a complex karyotype with ≥ 3 aberrations comprising a TP53 deletion. No recurrent molecular mutations or other fusions were identified, suggesting that ETV6::ACSL6 functions as a driver event in the pathogenesis of all cases. Five out of seven patients received intensive chemotherapy, including allogeneic hematopoietic transplantation (alloHCT) in 4 patients. The median overall survival of 5 patients with available follow-up was 11 months. We conclude that the reciprocal translocation t(5;12)(q32;p13) requires a careful and step-wise diagnostic work-up to differentiate between an underlying ETV6::PDGFRB fusion gene with associated excellent prognosis on imatinib and an ETV6::ACSL6 fusion gene, for which the prognosis is poor and alloHCT appears to be a promising therapeutic option.