Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited - PubMed (original) (raw)

Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited

Michaël Gué et al. BMC Cancer. 2006.

Abstract

Background: Haematological 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.

Methods: Using 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.

Results: In 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.

Conclusion: The 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.

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Figures

Figure 1

Figure 1

Example of 4-color images from simultaneous 3D-FISH experiments in NALM-6 cell nucleus. Labeled genes were MLL, AF4 and ENL represented by green, white and red spots respectively. Nuclear DNA stained with DAPI is displayed in blue.

Figure 2

Figure 2

2D – Plot of minimum value of measured distances between MLL to AF4 and MLL to ENL genes for all cells. Distances are expressed in μm. Vertical and horizontal blue lines symbolize the gene proximity criterion (2 μm) below which genes could be potentially translocated. Values express the percentage of cells in which the distances reported in one axis is smaller than the distance on the other axis. Grey areas correspond to nuclei where only one of gene could be translocated.

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