Duro D, Bernard O, Della Valle V, Leblanc T, Berger R, Larsen C J
Unité 301 INSERM, Centre National de la Recherche Scientifique, Institute of Molecular Genetics, Paris, France.
Cancer Res. 1996 Feb 15;56(4):848-54.
We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.
我们之前报道过一项关于B细胞急性淋巴细胞白血病中t(9;14)(p21 - 22; q11)的初步研究。这种易位重排了14号染色体q11带的TCRA/D基因座以及9号染色体p21带编码肿瘤抑制基因P16INK4/MTS1（P16）的基因座（D. Duro等人，《癌基因》，11: 21 - 29，1995）。在本报告中，断点被精确地定位在每个染色体伙伴上。在14号染色体q - 衍生体上，来自9号染色体的序列在P16第一个外显子上游1.0 kb处中断，靠近共有重组七聚体CACTGTG。此外，14号染色体断点位于TCRD2（δ2）区段末端，在易位连接处存在22个来源不明的残基。在9号染色体p + 衍生体上，9号染色体序列与转移到14号染色体上的序列连续，14q11断点位于TCRJA29区段内。这些特征与TCR基因重组酶复合体的异常活性一致。尽管P16的所有三个编码外显子都转移到了14号染色体q - 衍生体上，但在白血病细胞中未检测到P16转录本。由于跨越P16外显子1的区域未因甲基化而失活，且另一个P16等位基因被缺失，这意味着染色体断点可能破坏了参与该基因正常表达的调控元件。总体而言，我们的结果表明，影响9号染色体p21带的易位可能参与了P16的失活，因此有理由对急性淋巴细胞白血病中9号染色体p21带的易位进行系统研究。
