AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations
AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations
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DOI：
10.1038/modpathol.2009.156
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发表时间：
2010-02-01
期刊：
影响因子：
7.5
通讯作者：
Tinguely, Marianne
中科院分区：
文献类型：
--
作者：
Leuenberger, Mona;Frigerio, Simona;Tinguely, Marianne
慢性淋巴细胞白血病和小淋巴细胞淋巴瘤的生物学行为是不可预测的。然而，非突变的IgV(H)基因重排、ATM （11q22-23）和p53 （17p13）缺失被认为是慢性淋巴细胞白血病的不利预后因素。激活诱导胞苷脱氨酶（AID）的mRNA表达，是体细胞超突变过程中不可缺少的一种酶，据称可以预测血液中非突变的慢性淋巴细胞白血病细胞。在这里，我们使用组织微阵列方法评估了71例慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者中AID蛋白表达与已知分子和免疫组织化学预后指标的比较。通过对CD5和CD23的共定位分析，我们发现AID在肿瘤细胞中异质表达。增殖中心的副免疫母细胞Ki-67阳性表达最高。这一观察结果反映在AID阳性与高增殖率的显著关联上（P=0.012）。10%（6/63）的患者存在ATM缺失，19%（13/67）的患者存在p53缺失。此外，ATM （P=0.002）和p53缺失（P=0.004）与AID显著相关。45%（27/60）患者出现IgV(H)基因突变。25%（17/69）的艾滋病阳性慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者的生存期短于艾滋病阴性慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者（61个月vs 130个月，P=0.001）。虽然有趋势，但我们无法证明与IgV(H)基因突变状态有关。综上所述，我们的研究表明，AID表达是慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者预后不良的一个指标，尽管它不是IgV(H)状态的替代标志物。此外，扩散中心的微环境似乎影响了AID的调节，并可能是其转变的启动因素。现代病理学（2010）23,177-186；doi: 10.1038 / modpathol.2009.156;2009年11月6日在线发布
The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV(H) gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P=0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P=0.002) and p53 deletion (P=0.004) were significantly associated with AID. IgV(H) gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P=0.001). Although there was a trend, we could not show an association with the IgV(H) gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV(H) status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor in its transformation. Modern Pathology (2010) 23, 177-186; doi: 10.1038/modpathol.2009.156; published online 6 November 2009