43. Structural changes characterized by whole genome mate-pair sequencing in a case with ETV6/ABL1 gene fusion and atypical Chronic Myeloid Leukemia

      Gene fusions involving ABL1, leading to an abnormal tyrosine kinase, are oncogenic in hematological malignancies. Here, we reported a myeloproliferative neoplasm case with an ETV6/ABL1 gene fusion that resulted from a complex t(9;12)(q34;p13) translocation. The clinical features of the patient suggested chronic myeloid leukemia (CML) or chronic myelomonocytic leukemia (CMML). Chromosome and FISH analysis detected an apparently reciprocal translocation between the ETV6 and ABL1 loci, indicating a possible ETV6/ABL1 gene fusion. The patient was treated with tyrosine kinase inhibitors and had a good response, confirming an active ETV6/ABL1 gene fusion. However, how this active gene fusion was formed was unclear, since ETV6 and ABL1 would be in opposite orientations after a simple reciprocal translocation. To understand the mechanism of forming the active ETV6/ABL1 gene fusion, we further studied this case using whole genome mate-pair sequencing (MP-seq), which detected a paracentric inversion between CLEC4E and ETV6 on the short arm of chromosome 12 in conjunction with the t(9;12) translocation. This particular inversion altered the orientation of ETV6 on 12p, resulting in an in-frame and active ETV6/ABL1 gene fusion after the t(9;12) translocation. It is noteworthy that t(9;12) translocation involving the ETV6 and ABL1 genes is a rare but recurrent finding in hematological disorders. The inversion could be a common mechanism to form an active ETV6/ABL1 gene fusion. In addition, the MP-seq also revealed an apparently reciprocal t(1;15)(p34.2;q15) translocation and a 545 Kb interstitial deletion at 15q21.3. The HEYL and ZNF106 genes were involved in the t(1;15) translocation, and the PYGO1, NEDD4, and RFX7 genes were involved in the 15q21.3 deletion. While it is reasonable to assume that the patient's phenotype was due to the overall genomic changes in the leukemic cells, the pathogenic contribution of each gene/genomic change needs to be further evaluated.
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