Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients
Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients
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DOI：
10.1038/leu.2009.197
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发表时间：
2010-01-01
期刊：
影响因子：
11.4
通讯作者：
Martinelli, G.
中科院分区：
文献类型：
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作者：
Iacobucci, I.;Lonetti, A.;Martinelli, G.
BCR-ABL1阳性急性淋巴细胞白血病（ALL）临床结果不良的主要原因是遗传不稳定性。然而，正常 B 细胞前体如何获得导致转化的基因变化尚未完全明确。我们研究了 61 名成人 BCR-ABL1 阳性 ALL 患者中激活诱导的胞苷脱氨酶 (AID) 的表达及其在临床结果中的作用。 36 名患者（59%）检测到 AID 表达；它与 BCR-ABL1 转录水平相关，并在用酪氨酸激酶抑制剂治疗后消失。鉴定出不同的 AID 剪接变体：全长亚型； AID Delta E4a，外显子 4 缺失 30 bp； AID Delta E4，外显子 4 缺失； AIDins3，保留内含子 3； AID Delta E3-E4 亚型无脱氨酶活性。 AID-FL 主要显示细胞质定位，AID-Delta E4a 和 AID-Delta E3E4 变体也是如此，而 C 端截短的 AID-Delta E4 显示略微增加的核定位模式。 AID 表达与使用单核苷酸多态性阵列进行全基因组分析中发现的大量拷贝数改变相关。然而，诊断时 AID 的表达与较差的预后无关。总之，BCR-ABL1 阳性 ALL 细胞异常表达不同的 AID 亚型，这些亚型可能作为免疫球蛋白 (Ig) 基因位点外的突变子，促进遗传不稳定。白血病 (2010) 24, 66-73;doi:10.1038/leu.2009.197; 2009 年 9 月 17 日在线发布
The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AID Delta E4a, with a 30-bp deletion of exon 4; AID Delta E4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AID Delta E3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-Delta E4a and AID-Delta E3E4 variants, whereas the C-terminal-truncated AID-Delta E4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability. Leukemia (2010) 24, 66-73;doi:10.1038/leu.2009.197; published online 17 September 2009