IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia
IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia
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DOI：
10.1111/j.1365-2141.2006.05974.x
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发表时间：
2006-04-01
影响因子：
6.5
通讯作者：
Fais, F
中科院分区：
文献类型：
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作者：
Bagnara, D;Callea, V;Fais, F
在一个b细胞慢性淋巴细胞白血病（B-CLL）病例的白血病细胞中，免疫球蛋白（Ig）变量(V)基因的克隆内多样化在2年的四个时间点进行了评估。通过对B-CLL细胞IgV重(H)链和轻(C)链基因重排聚合酶链反应扩增得到的305个分子克隆进行测序，分析克隆内异质性。通过比较序列来评估克隆内变异和体细胞突变的性质。虽然在所有时间点都检测到IgV克隆内变异，但其水平随着时间的推移而下降，并且观察到平行出现了两个更具代表性的V(H)DJ(H)克隆。它们的不同之处在于9个核苷酸替换，其中一个只引起保守的替代氨基酸变化。此外，随着时间的推移，一种V(L)J(L)重排变得更加明显。体细胞突变分析提示抗原选择和肿瘤细胞负选择损伤。此外，还建立了一个代表肿瘤细胞克隆进化模型的谱系树。值得注意的是，在研究期间，患者表现出疾病的临床进展。我们得出结论，抗原刺激和体细胞超突变可能通过肿瘤亚克隆的选择和扩增参与疾病进展。
Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).