Antiapoptotic BCL-2 is required for maintenance of a model leukemia
Antiapoptotic BCL-2 is required for maintenance of a model leukemia
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DOI：
10.1016/j.ccr.2004.07.011
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发表时间：
2004-09-01
期刊：
影响因子：
50.3
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Letai, A;Sorcinelli, MD;Korsmeyer, SJ
对细胞凋亡的抵抗通常是通过抗凋亡蛋白的过度表达来实现的，这是常见的，并且可能是癌症发生所必需的。然而，凋亡缺陷是否对肿瘤维持至关重要尚不确定。为了验证这一点，我们培养了表达条件BCL-2基因和组成型c-myc的小鼠，这些小鼠发展为淋巴细胞白血病。消除BCL-2可迅速减少白血病细胞并显著延长生存期，正式证实BCL-2是癌症治疗的合理靶点。尽管存在或可能归因于其他致癌事件，但这种单分子的缺失导致细胞死亡。这提示了一个可推广的模型，其中癌症固有的畸变产生强直性死亡信号，如果没有必要的凋亡缺陷的反对，这些信号将杀死细胞。
Resistance to apoptosis, often achieved by the overexpression of antiapoptotic proteins, is common and perhaps required in the genesis of cancer. However, it remains uncertain whether apoptotic defects are essential for tumor maintenance. To test this, we generated mice expressing a conditional BCL-2 gene and constitutive c-myc that develop lymphoblastic leukemia. Eliminating BCL-2 yielded rapid loss of leukemic cells and significantly prolonged survival, formally validating BCL-2 as a rational target for cancer therapy. Loss of this single molecule resulted in cell death, despite or perhaps attributable to the presence of other oncogenic events. This suggests a generalizable model in which aberrations inherent to cancer generate tonic death signals that would otherwise kill the cell if not opposed by a requisite apoptotic defect(s).