Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.
Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.
复制标题
关注B-all：B细胞受体曲目揭示了从诊断到复发的许多B淋巴细胞白血病亚克隆的持久性。
DOI：
10.1038/leu.2016.142
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发表时间：
2016-12
期刊：
影响因子：
11.4
通讯作者：
Vassiliou GS
中科院分区：
文献类型：
--
作者：
Bashford-Rogers RJ;Nicolaou KA;Bartram J;Goulden NJ;Loizou L;Koumas L;Chi J;Hubank M;Kellam P;Costeas PA;Vassiliou GS
B细胞急性淋巴细胞白血病（B-ALL）复发的最强预测因子是初始治疗后肿瘤细胞的持续存在水平。B细胞受体（BCR）基因座的高突变率允许高分辨率跟踪B-ALL的结构，进化和克隆动力学。使用纵向BCR库测序，我们发现BCR通过体细胞超突变和二级重排在B-ALL细胞中经历了意想不到的高水平克隆多样化，这可以用于跟踪疾病的亚克隆组成，并以前所未有的灵敏度检测微小残留病。我们继续研究B-ALL的克隆动力学，使用配对诊断-复发样本的BCR系统发育分析，发现诊断时存在的大量小白血病亚克隆在复发时与显性克隆一起重新出现。我们的研究结果表明，在所有信息复发患者中，大量克隆形成细胞在初始化疗后的存活是固有的部分化疗耐药或治疗不足的替代品，为随后出现完全耐药克隆提供了更多的机会。这些结果将早期细胞减灭术作为长期结果的重要决定因素。
The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.