Characterisation of genomic translocation breakpoints and identification of an alternative TCF3/PBX1 fusion transcript in t(1;19)(q23;p13)-positive acute lymphoblastic leukaemias.

The t(1;19)(q23;p13), one of the most common translocations in childhood and adult acute lymphoblastic leukaemias (ALLs), usually results in fusion of exons 1-16 of TCF3 (previously E2A) and exons 3-9 of PBX1. However, some t(1;19)-positive ALLs are negative for this chimaera. We here report an alternative TCF3/PBX1 transcript, fusing exon 17 of TCF3 with exon 5 of PBX1, in a paediatric t(1;19)-positive ALL. The different breakpoints made this hybrid undetectable by reverse transcription polymerase chain reaction using standard TCF3 and PBX1 primers. Hence, ALLs with t(1;19) that test negative for TCF3/PBX1 should be analysed further before excluding this alternative fusion. Furthermore, we have characterised the genomic translocation breakpoints in eight TCF3/PBX1-positive ALLs; four cases with a balanced t(1;19) and four with an unbalanced der(19)t(1;19). It has previously been suggested that the breakpoints are clustered, particularly in TCF3, and that N-nucleotides are frequently present in the fusion junctions. Three of seven investigated TCF3 intron 16 breakpoints were within the previously described 14 base pair-cluster, and all but two junctions harboured N-nucleotides. The PBX1 breakpoints were more dispersed, although still clustered in two regions. This confirms that most t(1;19) rearrangements may arise by a combination of illegitimate V(D)J recombination and non-homologous end joining.