4. ETV6-ABL1 variant rearrangement described in a childhood ALL patient

      Rearrangements involving ETV6 and ABL1 are more commonly observed in Philadelphia-negative myeloproliferative neoplasms, with rare reports in patients with AML or ALL. We present the evaluation of a 12-year old male who presented with acute fever and a CBC which showed progressive anemia. Bone marrow analysis identified precursor B-cell ALL. Chromosome, fluorescence in situ hybridization (FISH) and SNP CMA analyses were performed on cells from a bone marrow aspirate. Chromosome analysis identified a slightly atypical hyperdiploid ALL clone [51,XY,+X,+15,+17,+21,+21]. Interphase FISH showed two signals for chromosomes 4 and 10, four RUNX1 signals, negativity for KMT2A rearrangement and BCR/ABL1 or ETV6/RUNX1 fusions. However, one ETV6 signal was clearly diminished in addition to a deletion of one ASS1 9q34 probe signal. We have previously associated the latter with either ABL1 or NUP214 9q34 gene fusions typically seen in T-ALL, which can be resolved by microarray, RNA sequencing, or dual-color FISH. A SNP microarray confirmed the chromosome gains observed in the karyotype and revealed that the ASS1 deletion included partial deletion of ABL1 distally but no specific gene proximally, suggesting an ectopic gene insertion, resulting in a probable ABL1 fusion. The array was notable for a contiguous terminal deletion and proximal duplication of 12p. Although ETV6 was located in the deleted interval, there was an increased copy number for ∼90% of the gene. This was interpreted as strong evidence of ETV6 insertion into chromosome 9. Since both ETV6 and ABL1 have opposite orientation to the centromeres, an in-frame fusion gene requires three chromosome breaks to be generated (limiting the incidence of this fusion) and the putative insertion mechanism in this clone would be consistent with that etiology. An ETV6/ABL1 fusion within 9q34 was confirmed by metaphase FISH and RNA sequencing. This report highlights the utility of a multidiscipline approach to leukemia evaluation.
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