Targeting B-cell anergy in chronic lymphocytic leukemia
Targeting B-cell anergy in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2012-12-474718
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发表时间：
2013-05-09
期刊：
影响因子：
20.3
通讯作者：
Caligaris-Cappio, Federico
中科院分区：
文献类型：
--
作者：
Apollonio, Benedetta;Scielzo, Cristina;Caligaris-Cappio, Federico
B细胞受体（BCR）的触发和反应性在慢性淋巴细胞白血病（CLL）克隆的存活和扩增中起着至关重要的作用。CLL细胞对BCR触发的体外反应分析允许定义2个主要的患者亚群，信号传导能力的缺乏与细胞外调节激酶1/2（ERK 1/2）和活化T细胞核因子c1（NF-ATc 1）的组成性活化相关，这与至少一组CLL患者来源于无反应性B细胞的异常扩增的观点一致。在目前的工作中，我们进一步研究了CLL的无反应性亚群（定义为具有组成性ERK 1/2磷酸化的亚群），发现其特征在于低水平的表面免疫球蛋白M和体外BCR参与后钙动员受损。在磷酸化ERK 1/2样品中，慢性BCR触发选择性地促进CLL细胞存活，并且在该组患者中使用促分裂原活化蛋白激酶和NF-AT信号传导抑制剂特异性地诱导细胞凋亡。细胞凋亡诱导之前的初始阶段的无能逆转组成的ERK磷酸化和NF-AT核转位的损失和恢复BCR的反应，加强的想法，无能程序有利于白血病淋巴细胞的生存。
B-cell receptor (BCR) triggering and responsiveness have a crucial role in the survival and expansion of chronic lymphocytic leukemia (CLL) clones. Analysis of in vitro response of CLL cells to BCR triggering allowed the definition of 2 main subsets of patients and lack of signaling capacity was associated with constitutive activation of extracellular-regulated kinases 1/2 (ERK1/2) and nuclear factor of activated T cells c1 (NF-ATc1), consistent with the idea that at least one group of CLL patients derives from the abnormal expansion of anergic B cells. In the present work, we further investigated the anergic subset of CLL (defined as the one with constitutive ERK1/2 phosphorylation) and found that it is characterized by low levels of surface immunoglobulin M and impairment of calcium mobilization after BCR engagement in vitro. Chronic BCR triggering promoted CLL cell survival selectively in phosphorylated ERK1/2 samples and the use of mitogen-activated protein kinase and NF-AT signaling inhibitors specifically induced apoptosis in this group of patients. Apoptosis induction was preceded by an initial phase of anergy reversal consisting in the loss of ERK phosphorylation and NF-AT nuclear translocation and by the restoration of BCR responsiveness, reinforcing the idea that the anergic program favors the survival of leukemic lymphocytes.