Complex Genomic Rearrangements Involving ETV6::ABL1 Gene Fusion in an Individual with Myeloid Neoplasm

Abstract

ETV6::ABL1 gene fusion is a rare recurrent genomic rearrangement associated with hematologic malignancies, and frequently occurs with additional anomalies. Due to the opposite chromosome orientations of the ETV6 and ABL1 genes, an oncogenic in-frame ETV6::ABL1 gene fusion cannot be formed by a simple translocation. The molecular mechanism of the ETV6::ABL1 fusion and the significance of co-occurring anomalies are not fully understood. We characterized genomic alterations in an individual with ETV6::ABL1 gene-fusion-positive myeloid neoplasm using various genomic technologies. Our findings uncovered a molecular mechanism of the ETV6::ABL1 fusion, in which a paracentric inversion within the short arm of chromosome 12 (12p) and a translocation between the long arm of a chromosome 9 and the 12p with the inversion were involved. In addition, we detected multiple additional anomalies in the individual, and our findings suggested that the ETV6::ABL1 fusion occurred as a secondary event in a subset of cells with the additional anomalies. We speculate that the additional anomalies may predispose to further pathogenic changes, including ETV6::ABL1 fusion, leading to neoplastic transformation.

ETV6::ABL1-Positive Myeloid Neoplasm: A Case of a Durable Response to Imatinib Mesylate without Additional or Previous Treatment

“…Conventional diagnostic techniques (such as conventional cytogenetics) sometimes fail to detect this rearrangement because of its cryptic nature due to the similar G-banding pattern of the distal long arm of chromosome 9 and the distal short arm of chromosome 12. Moreover, no ready-to-use ETV6::ABL1 FISH probes are commercially available, suggesting that the ETV6-ABL1 fusion may remain undetected in a number of patients [ 5 , 11 ].…”

“…ETV6::ABL1 (also known as TEL :: ABL1 ) is a rare fusion that has been found in different types of hematological diseases. To date, about 80 cases of hematological neoplasms (more frequently, acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms (MPNs), Philadelphia-negative chronic myeloid leukemia (CML) [ 1 ], atypical (a)CML and chronic myelomonocytic leukemia (CMML)) carrying ETV6::ABL1 translocation have been reported [ 2 , 3 , 4 , 5 , 6 ]. ETV6::ABL1 chimeric protein has been found in less than 1% of ALL cases; however, due to the lack of a systematic screening for this fusion transcript, its overall incidence in hematological neoplasms cannot be precisely defined [ 2 ].…”