在 B 细胞慢性淋巴细胞白血病和非霍奇金淋巴瘤中，SET 癌蛋白过表达：侵袭性疾病的预测因子和新的治疗靶点。
SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.
机构信息
Oncotide Pharmaceuticals, Durham, NC, USA.
出版信息
Blood. 2011 Oct 13;118(15):4150-8. doi: 10.1182/blood-2011-04-351072. Epub 2011 Aug 15.
Abstract
B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.
摘要
B 细胞慢性淋巴细胞白血病（CLL）是一种无法治愈的白血病，其特征是凋亡缺陷。我们发现 SET 癌蛋白在原发性 CLL 细胞和 B 细胞非霍奇金淋巴瘤（NHL）细胞系细胞中过度表达，是一种有效的蛋白磷酸酶 2A（PP2A）肿瘤抑制因子抑制剂。在 CLL 中，SET 的水平升高与疾病的严重程度显著相关（治疗时间和总生存期更短）。我们开发了与 SET 结合、增加细胞内 PP2A 活性、降低 Mcl-1 表达的 SET 拮抗剂肽，并在体外对 CLL 和 NHL 细胞显示出选择性细胞毒性。此外，SET 的 shRNA 在体外对 NHL 细胞具有细胞毒性。SET 拮抗剂肽 COG449 抑制了小鼠 NHL 肿瘤异种移植物的生长。这些数据表明 SET 是 B 细胞恶性肿瘤的一个新的治疗靶点，SET 拮抗剂代表了治疗 CLL 和 NHL 的新型药物。
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