Abstract
BackgroundHaematological cancer is characterised by chromosomal translocation (e.g. MLL translocation in acute leukaemia) and two models have been proposed to explain the origins of recurrent reciprocal translocation. The first, established from pairs of translocated genes (such as BCR and ABL), considers the spatial proximity of loci in interphase nuclei (static "contact first" model). The second model is based on the dynamics of double strand break ends during repair processes (dynamic "breakage first" model). Since the MLL gene involved in 11q23 translocation has more than 40 partners, the study of the relative positions of the MLL gene with both the most frequent partner gene (AF4) and a less frequent partner gene (ENL), should elucidate the MLL translocation mechanism.MethodsUsing triple labeling 3D FISH experiments, we have determined the relative positions of MLL, AF4 and ENL genes, in two lymphoblastic and two myeloid human cell lines.ResultsIn all cell lines, the ENL gene is significantly closer to the MLL gene than the AF4 gene (with P value < 0.0001). According to the static "contact first" model of the translocation mechanism, a minimal distance between loci would indicate a greater probability of the occurrence of t(11;19)(q23;p13.3) compared to t(4;11)(q21;q23). However this is in contradiction to the epidemiology of 11q23 translocation.ConclusionThe simultaneous multi-probe hybridization in 3D-FISH is a new approach in addressing the correlation between spatial proximity and occurrence of translocation. Our observations are not consistent with the static "contact first" model of translocation. The recently proposed dynamic "breakage first" model offers an attractive alternative explanation.
Highlights
Haematological cancer is characterised by chromosomal translocation (e.g. Mixed Lineage Leukaemia (MLL) translocation in acute leukaemia) and two models have been proposed to explain the origins of recurrent reciprocal translocation
The Mixed Lineage Leukaemia (MLL) gene on chromosome band 11q23 is a recurrent target of reciprocal translocation in human acute leukaemias
Another frequent partner of translocation is the ENL gene located on band 19p13.3, but whilst translocation t(11;19)(q23;p13.3) is found in both acute lymphoblastic leukemia (ALL) and acute myelogenous leukaemia (AML), it represents only 6% of all MLL translocations
Summary
The ENL gene is significantly closer to the MLL gene than the AF4 gene (with P value < 0.0001). According to the static "contact first" model of the translocation mechanism, a minimal distance between loci would indicate a greater probability of the occurrence of t(11;19)(q23;p13.3) compared to t(4;11)(q21;q23). This is in contradiction to the epidemiology of 11q23 translocation
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