Gué Michaël, Sun Jian-Sheng, Boudier Thomas
USM 0503, Département Régulations, Développement et Diversité Moléculaire, Muséum National d'Histoire Naturelle, UMR 5153 CNRS-MNHN, U 565 INSERM, 43 rue Cuvier, CP26, 75231 Paris Cedex 05, France.
BMC Cancer. 2006 Jan 24;6:20. doi: 10.1186/1471-2407-6-20.
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.
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.
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.
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.
血液系统癌症的特征是染色体易位（如急性白血病中的MLL易位），并且已经提出了两种模型来解释复发性相互易位的起源。第一种模型是基于成对的易位基因（如BCR和ABL）建立的，它考虑了间期核中基因座的空间接近性（静态“接触优先”模型）。第二种模型基于修复过程中双链断裂末端的动力学（动态“断裂优先”模型）。由于参与11q23易位的MLL基因有40多个伙伴基因，因此研究MLL基因与最常见伙伴基因（AF4）和较不常见伙伴基因（ENL）的相对位置，应该能够阐明MLL易位机制。
我们使用三重标记3D-FISH实验，确定了MLL、AF4和ENL基因在两种淋巴细胞系和两种髓细胞系中的相对位置。
在所有细胞系中，ENL基因比AF4基因更接近MLL基因（P值<0.0001）。根据易位机制的静态“接触优先”模型，基因座之间的最小距离表明与t(4;11)(q21;q23)相比，t(11;19)(q23;p13.3)发生的可能性更大。然而，这与11q23易位的流行病学情况相矛盾。
3D-FISH中的同步多探针杂交是一种解决空间接近性与易位发生之间相关性的新方法。我们的观察结果与易位的静态“接触优先”模型不一致。最近提出的动态“断裂优先”模型提供了一个有吸引力的替代解释。
