The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells
The B lineage transcription factor E2A regulates apoptosis in chronic lymphocytic leukemia (CLL) cells
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DOI：
10.1093/intimm/dxr027
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发表时间：
2011-06-01
影响因子：
4.4
通讯作者：
Borghesi, Lisa
中科院分区：
文献类型：
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作者：
Kardava, Lela;Yang, Qi;Borghesi, Lisa
慢性淋巴细胞性白血病(CLL)是一种常见的恶性肿瘤，其特征是B淋巴细胞积聚抗原激活的CD19(+)CD5(+)克隆性表型。临床上，类似于50%的病例会表现得更具侵略性。在这里，我们研究了主要的B细胞转录因子E2a对CLL持久性的作用。E2a是已知的B细胞生存和增殖的调节因子。我们发现，相对于正常的B细胞亚群，E2A在mRNA和蛋白质水平上都是升高的。在CD38(+)(侵袭性)和CD38(-)(惰性)病例中，原代CLL细胞中E2A的沉默导致自发凋亡的显著增加。此外，E2A基因敲除与免疫调节药物来那度胺协同作用可降低CLL的存活率。已知E2A可在多个成熟阶段抑制原代B和T淋巴细胞的增殖，我们报道，在不影响从头开始的增殖的情况下，靶向干扰E2A会增加Ki-67(+)CLL细胞的频率。在分子水平上，经E2AsiRNA处理的CLL细胞表现出与生存和细胞周期相关的关键基因表达降低，包括p27、p21和mcl1，其中前两个是已知的E2A靶基因。因此，E2a是与B细胞激活相关的关键转录因子，调节CLL中的细胞凋亡，可能与疾病的病理有关。
Chronic lymphocytic leukemia (CLL) is a common malignancy characterized by the accumulation of B lymphocytes with an antigen-experienced activated CD19(+)CD5(+) clonal phenotype. Clinically, similar to 50% of cases will behave more aggressively. Here, we investigate the role of the major B-cell transcription factor E2A, a known regulator of B-cell survival and proliferation, to CLL persistence. We show that E2A is elevated at the mRNA and protein levels relative to normal B-cell subsets. E2A silencing in primary CLL cells leads to a significant increase in spontaneous apoptosis in both CD38(+) (aggressive) and CD38(-) (indolent) cases. Moreover, E2A knockdown synergizes with the immunomodulatory drug lenalidomide to reduce CLL viability. E2A is known to restrain the proliferation of primary B and T lymphocytes at multiple stages of maturation and we report that targeted E2A disruption increases the frequency of Ki-67(+) CLL cells in the absence of effects on de novo proliferation. At the molecular level, E2A siRNA-treated CLL cells display reduced expression of key genes associated with survival and cell cycling including p27, p21 and mcl-1, of which the former two are known E2A target genes. Thus, E2A, a key transcription factor associated with the B-cell activation profile, regulates apoptosis in CLL and may contribute to disease pathology.