Petrinelli P, Elli R, Marcucci L, Tabolacci E, Barbieri C, Antonelli A
Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università "La Sapienza", Rome, Italy.
Cancer Genet Cytogenet. 2001 Feb;125(1):46-51. doi: 10.1016/s0165-4608(00)00358-7.
T-cell tumors in ataxia telangiectasia (AT), such as T-PLL/T-CLL, are first preceded by the development of a large clone of T-lymphocytes, characterized by chromosomal rearrangements, which usually involve specific regions such as the 14q11 region. Malignancy develops years later, after additional chromosomal changes resulting from the genomic instability consequent to ATM disruption and to the activation of the TCL1 oncogene. Here we report the results of a cytogenetic follow-up of an AT patient (AT94-1), still without signs of hematological abnormalities, bearing a T-lymphocyte clone characterized by the t(14;14)(q11;q32) rearrangement and having TCL1 expression. We demonstrated that in clonal cells TCL1 expression correlates with increasing genomic instability and in time this mainly induces chromosomal rearrangements and telomeric associations (tas). Chromosome 21 is not randomly involved; in particular, an i(21q) indicates that it is a subclone prone to additional genetic changes and could represent an early chromosomal rearrangement involved in tumorigenesis. With regard to the increase in tas, we observed that: (i) it is inversely correlated with the proliferative ability of AT94-1 lymphocytes in PHA-stimulated short-term cultures (cell aging in vitro); (ii) this increase is not due to changes either in cell radiosensitivity (measured as bleomycin (BML)-sensitivity) or due to an illegitimate recombination (measured as adriamycin-sensitivity), which may not be sufficient for tumor development.
共济失调毛细血管扩张症（AT）中的T细胞肿瘤，如T-PLL/T-CLL，首先是由一大群T淋巴细胞的发展引发的，其特征是染色体重排，通常涉及特定区域，如14q11区域。数年之后，由于ATM功能缺失导致基因组不稳定以及TCL1癌基因激活引发额外的染色体变化，恶性肿瘤才会发生。在此，我们报告了对一名AT患者（AT94-1）进行细胞遗传学随访的结果，该患者仍无血液学异常迹象，携带一个以t(14;14)(q11;q32)重排为特征且表达TCL1的T淋巴细胞克隆。我们证明，在克隆细胞中，TCL1表达与基因组不稳定性增加相关，并且随着时间推移，这主要诱导染色体重排和端粒联合（tas）。21号染色体并非随机受累；特别是，一条i(21q)表明它是一个易于发生额外基因变化的亚克隆，可能代表肿瘤发生过程中早期的染色体重排。关于tas的增加，我们观察到：（i）它与PHA刺激的短期培养中AT94-1淋巴细胞的增殖能力呈负相关（体外细胞衰老）；（ii）这种增加既不是由于细胞放射敏感性的变化（以博来霉素（BML）敏感性衡量），也不是由于非法重组（以阿霉素敏感性衡量），这两者可能不足以引发肿瘤发展。
