Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia
Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia
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NFAT2表达缺失导致慢性淋巴细胞白血病克隆进化加速
DOI：
10.1002/jlb.2ab0218-076rr
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发表时间：
2018
影响因子：
5.5
通讯作者：
Muller Martin R.
中科院分区：
文献类型：
--
作者：
Muller David J.;Wirths Stefan;Fuchs Alexander R.;Marklin Melanie;Heitmann Jonas S.;Sturm Marc;Haap Michael;Kirschniak Andreas;Sasaki Yoshiteru;Kanz Lothar;Kopp Hans-Georg;Muller Martin R.
慢性淋巴细胞白血病（CLL）可定义为具有定型BCR的B细胞的克隆性扩增。BCR重链的体细胞超突变（IGVH）定义了预后较好的患者亚组。在高达10%的CLL病例中，随着时间的推移，可以观察到转化为侵袭性B细胞淋巴瘤（Richter综合征），预后不良。NFAT蛋白是最初在T细胞中鉴定的转录因子，其在B细胞中也起重要作用。TCL1转基因小鼠是公认的CLL模型。在NFAT 2的B细胞特异性缺失后，TCL1转基因小鼠发展出类似于人Richter综合征的疾病。尽管TCL1 B细胞表现出人CLL的紧张性无反应性BCR信号传导特征，但NFAT 2表达的丧失导致容易活化的BCR，表明不同的BCR使用与改变的下游信号传导。在这里，我们分析了野生型和TCL1转基因小鼠和无NFAT 2缺失采用传统的分子生物学技术和下一代测序（NGS）的BCR使用。我们证明，在CLL沉淀的NFAT 2的损失选择未突变的BCR和某些VDJ重组的优先使用，这随后导致寡克隆疾病的加速发展。
Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter’s syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter’s syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.