Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias
Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias
复制标题
DOI：
10.1038/sj.leu.2404008
复制
发表时间：
2006-01-01
期刊：
影响因子：
11.4
通讯作者：
Soulier, J
中科院分区：
文献类型：
--
作者：
Clappier, E;Cuccuini, W;Soulier, J
三种D型细胞周期蛋白中至少一种的强表达在人类癌症中很常见。虽然细胞周期蛋白D1和D3基因（CCND 1和CCND 3）经常参与基因组重排，特别是在B细胞淋巴瘤，没有明确的参与细胞周期蛋白D2基因（CCND 2）已被报道。在这里，我们确定了靶向12 p13处CCND 2基因座和T细胞受体β（TCRB）或T细胞急性淋巴细胞白血病（T-ALL）中TCRA/D基因座的染色体易位。表达分析表明，与其他T-ALL（总计，n = 89）相比，易位病例（n=3）中细胞周期蛋白D2过度表达。为了评估T-ALL相对于正常T细胞分化的失调，我们分析了正常纯化人胸腺亚群中的CCND 2表达。CCND 2水平通过从人类T细胞分化的早期阶段的进展而下调，进一步表明CCND 2重排的T-ALL病例中的大量和持续表达是致癌的。与其他癌基因表达（TAL 1、HOXAs或TLX 3/HOX 11 L2）、NOTCH 1激活突变和/或CDKN 2A/p16/ARF缺失的相关性表明，细胞周期蛋白D2失调可能导致各种T-ALL组的多事件肿瘤发生。这份报告是第一个明确的证据表明，细胞周期蛋白D2直接参与人类癌症由于经常性的体细胞遗传变异。
Strong expression of at least one of the three D-type cyclins is common in human cancers. While the cyclin D1 and D3 genes (CCND1 and CCND3) are recurrently involved in genomic rearrangements, especially in B-cell lymphoid neoplasias, no clear involvement of the cyclin D2 gene (CCND2) has been reported to date. Here, we identified chromosomal translocations targeting the CCND2 locus at 12p13, and the T-cell receptor beta (TCRB) or the TCRA/D loci in T-cell acute lymphoblastic leukemias (T-ALLs). Expression analysis demonstrated dramatic cyclin D2 overexpression in the translocated cases (n=3) compared to other T-ALLs ( total, n = 89). In order to evaluate dysregulation in T-ALL with respect to normal T-cell differentiation, we analyzed CCND2 expression in normal purified human thymic subpopulations. CCND2 levels were downregulated through progression from the early stages of human T-cell differentiation, further suggesting that the massive and sustained expression in the CCND2-rearranged T-ALL cases was oncogenic. Association with other oncogene expression (TAL1, HOXAs, or TLX3/HOX11L2), NOTCH1 activating mutations, and/or CDKN2A/p16/ARF deletion, showed that cyclin D2 dysregulation could contribute to multi-event oncogenesis in various T-ALL groups. This report is the first clear evidence of a direct involvement of cyclin D2 in human cancer due to recurrent somatic genetic alterations.