Ectopic expression of the HLXB9 gene is associated with an altered nuclear position in t(7;12) leukaemias

The t(7;12) rearrangement has been found in approximately one third of acute myeloid leukaemia (AML) in early childhood. In this study, we analysed seven patients characterised by the presence of a t(7;12)(q36;p13). We detected a fusion transcript HLXB9-ETV6 in four of these patients, whereas an over-expression of the HLXB9 gene was observed in all of the t(7;12) cases. Our hypothesis implies that leukaemogenesis via a chimeric protein is unlikely in these cases. As an alternative, we suggest a possible position effect mechanism. A growing number of studies indicate that the higher-order chromatin arrangement is related to gene expression. Hence, we expected that an altered expression pattern of the genes localized near the breakpoint would correspond to an altered radial nuclear location of the regions involved in the t(7;12). Our data show a shift in the radial position of the translocated HLXB9 gene (in 7q36), from the periphery to a more internal nuclear location. These data not only support the relevance of nuclear position in gene expression, but for the first time highlight the interplay between chromosome translocations, gene expression and nuclear repositioning to explain a mechanism at the basis of leukaemogenesis.