Reduced Level of the BCL11B Protein Is Associated with Adult T-Cell Leukemia/Lymphoma

BackgroundAdult T-cell leukemia/lymphoma (ATLL) develops in a small proportion of human T-cell leukemia virus type I (HTLV-I)-infected individuals. However, the mechanism by which HTLV-I causes ATLL has not been fully elucidated. To provide fundamental insights into the multistep process of leukemogenesis, we have mapped the chromosomal abnormalities in 50 ATLL cases to identify potential key regulators of ATLL.
ResultsThe analysis of breakpoints in one ATLL case with the translocations t(14;17)(q32;q22-23) resulted in the identification of a Kruppel zinc finger gene, BCL11B, which plays a crucial role in T-cell development. Among the 7 ATLL cases that we examined by immunofluorescence analysis, 4 displayed low and one displayed moderate BCL11B signal intensities. A dramatically reduced level of the BCL11B protein was also found in HTLV-I-positive T-cell lines. The ectopic expression of BCL11B resulted in significant growth suppression in ATLL-derived cell lines but not in Jurkat cells.
ConclusionsOur genetic and functional data provide the first evidence that a reduction in the level of the BCL11B protein is a key event in the multistep progression of ATLL leukemogenesis.

背景：成人T细胞白血病/淋巴瘤（Adult T-cell leukemia/lymphoma, ATLL）仅在一小部分感染人类T细胞白血病病毒I型（Human T-cell leukemia virus type I, HTLV-I）的个体中发生。然而，HTLV-I诱发ATLL的具体机制尚未完全阐明。为了深入解析白血病发生的多步骤进程的基础机制，我们对50例ATLL病例的染色体异常进行了定位分析，以识别ATLL潜在的关键调控因子。
结果：我们对1例携带t(14;17)(q32;q22-23)易位的ATLL病例的断裂点进行分析，成功鉴定出Kruppel锌指基因BCL11B，该基因在T细胞发育过程中发挥关键作用。在我们通过免疫荧光分析检测的7例ATLL病例中，4例呈现BCL11B信号强度降低，1例呈现中等强度的信号。同时，在HTLV-I阳性T细胞系中也检测到BCL11B蛋白水平显著降低。异位表达BCL11B可显著抑制ATLL来源细胞系的增殖，但对Jurkat细胞无此效应。
结论：我们的遗传学与功能学数据首次证实，BCL11B蛋白水平降低是ATLL白血病发生多步骤进展过程中的关键事件。