Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia.

We describe four cases of childhood B-cell progenitor acute lymphoblastic leukaemia (BCP-ALL) and one of T-cell (T-ALL) with unexpected numbers of interphase signals for ETV6 with an ETV6-RUNX1 fusion probe. Three fusion negative cases each had a telomeric part of 12p terminating within intron 2 of ETV6, attached to sequences from 5q, 7p and 7q, respectively. Two fusion positive cases, with partial insertions of ETV6 into chromosome 21, also had a breakpoint in intron 2. Fluorescence in situ hybridisation (FISH), array comparative genomic hybridization (aCGH) and Molecular Copy-Number Counting (MCC) results were concordant for the T-cell case. Sequences downstream of TLX3 on chromosome 5 were deleted, leaving the intact gene closely apposed to the first two exons of ETV6 and its upstream promoter. qRT-PCR showed a significant upregulation of TLX3. In this study we provide the first incontrovertible evidence that the upstream promoter of ETV6 attached to the first two exons of the gene was responsible for the ectopic expression of a proto-oncogene that became abnormally close as the result of deletion and translocation. We have also shown breakpoints in intron 2 of ETV6 in two cases of insertion with ETV6-RUNX1 fusion.