Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course.
Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course.
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DOI：
10.3389/fonc.2021.640731
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发表时间：
2021
影响因子：
4.7
通讯作者：
Chiorazzi N
中科院分区：
文献类型：
--
作者：
Bagnara D;Tang C;Brown JR;Kasar S;Fernandes S;Colombo M;Vergani S;Mazzarello AN;Ghiotto F;Bruno S;Morabito F;Rai KR;Kolitz JE;Barrientos JC;Allen SL;Fais F;Scharff MD;MacCarthy T;Chiorazzi N
慢性淋巴细胞白血病（CLL）IGHV基因突变的分析对该病的诊断和治疗有重要影响。IGHV突变状态的一个标志是它很少随时间发生克隆性变化。然而，IGHV-IGHD-IGHJ区域的靶向和深度DNA测序揭示了克隆内异质性。我们使用了一种DNA测序方法，该方法实现了相当大的深度，并最大限度地减少了伪影和扩增偏倚，以在长期随访的患者中鉴定IGHV-IGHD-IGHJ亚克隆。我们的研究结果扩展了以前的研究，揭示了几乎所有CLL克隆内IGHV-IGHD-IGHJ多样化。此外，他们指出，一些亚克隆与额外的IGHV-IGHD-IGHJ突变可以成为一个大部分的白血病负荷，达到单克隆B细胞淋巴细胞增多症的数值标准。值得注意的是，转化后IGHV-IGHD-IGHJ异质性的发生和复杂性以及多样化亚克隆的扩增在U-CLL和M-CLL患者中相似。亲本临床显性CLL克隆（CDC）中存在的突变的分子特征与转化后（CDC后）发生的突变不同。CDC后突变表现出显著更低的携带活化诱导的脱氨酶（AID）和Polη易错修复特征的突变分数，并且大多数突变不归因于这些酶。此外，与颠换相比，CDC后突变显示出较低的核苷酸转换百分比，这也不像AID的作用。最后，CDC后突变导致VH CDR中置换与沉默突变的比率显著降低，VH FR中的比率较高，这与经历AIDS介导过程的正常B细胞亚群中发现的突变分布不同。基于这些研究结果，我们提出，在CLL细胞的转化后突变要么反映了一个功能失调的标准体细胞突变过程或指向另一个突变过程的行动，以前不与IG V基因位点。如果是前一种情况，CDC后突变可能导致对抗原依赖性BCR信号传导的依赖性降低，并可能导致脱靶、非IG基因组突变的影响更大。或者，后一种活性可以增加由BCR通过结构改变的FR介导的新的刺激性存活/生长优势，例如通过超抗原结合和刺激发生的优势。
Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ regions has revealed intraclonal heterogeneity. We used a DNA sequencing approach that achieves considerable depth and minimizes artefacts and amplification bias to identify IGHV-IGHD-IGHJ subclones in patients with prolonged temporal follow-up. Our findings extend previous studies, revealing intraclonal IGHV-IGHD-IGHJ diversification in almost all CLL clones. Also, they indicate that some subclones with additional IGHV-IGHD-IGHJ mutations can become a large fraction of the leukemic burden, reaching numerical criteria for monoclonal B-cell lymphocytosis. Notably, the occurrence and complexity of post-transformation IGHV-IGHD-IGHJ heterogeneity and the expansion of diversified subclones are similar among U-CLL and M-CLL patients. The molecular characteristics of the mutations present in the parental, clinically dominant CLL clone (CDC) differed from those developing post-transformation (post-CDC). Post-CDC mutations exhibit significantly lower fractions of mutations bearing signatures of activation induced deaminase (AID) and of error-prone repair by Polη, and most of the mutations were not ascribable to those enzymes. Additionally, post-CDC mutations displayed a lower percentage of nucleotide transitions compared with transversions that was also not like the action of AID. Finally, the post-CDC mutations led to significantly lower ratios of replacement to silent mutations in VH CDRs and higher ratios in VH FRs, distributions different from mutations found in normal B-cell subsets undergoing an AID-mediated process. Based on these findings, we propose that post-transformation mutations in CLL cells either reflect a dysfunctional standard somatic mutational process or point to the action of another mutational process not previously associated with IG V gene loci. If the former option is the case, post-CDC mutations could lead to a lesser dependence on antigen dependent BCR signaling and potentially a greater influence of off-target, non-IG genomic mutations. Alternatively, the latter activity could add a new stimulatory survival/growth advantage mediated by the BCR through structurally altered FRs, such as that occurring by superantigen binding and stimulation.
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影响因子：
15.9
作者：
Fais, F;Ghiotto, F;Chiorazzi, N
通讯作者：
Chiorazzi, N
DOI：
10.1038/nrdp.2016.96
发表时间：
2017-01-19
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Kipps TJ;Stevenson FK;Wu CJ;Croce CM;Packham G;Wierda WG;O'Brien S;Gribben J;Rai K
通讯作者：
Rai K
影响因子：
6.5
作者：
Bagnara, D;Callea, V;Fais, F
通讯作者：
Fais, F
影响因子：
28.2
作者：
Heinig, Kristina;Gaetjen, Marcel;Hoepken, Uta E.
通讯作者：
Hoepken, Uta E.
影响因子：
20.3
作者：
Hallek, Michael;Cheson, Bruce D.;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.