Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells.
Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells.
复制标题
慢性 B 淋巴细胞白血病细胞中 DNA 片段化的诱导。
作者：
David J. McConkey;M. Aguilar;Pia Hartzell;Ina Eriksson;Håkan Mellstedt;S. Orrenius;Mikael Jondal
B细胞型慢性淋巴细胞性白血病（B-CLL）是一种肿瘤性疾病，其特征在于小的静息淋巴细胞在外周中积聚。这些细胞的表型表明它们在成熟的早期阶段被“冷冻”。糖皮质激素常用于治疗B-CLL患者，导致外周淋巴细胞计数减少，但机制不明。在这里，我们报告，糖皮质激素刺激DNA断裂的自杀过程中被称为细胞凋亡或程序性细胞死亡（PCD）的悬浮液中的细胞与B-CLL患者的特征。的影响可以模仿的Ca 2+离子载体，并涉及持续增加的胞质Ca 2+浓度。与白血病细胞上的膜相关IgM结合的特异性抗体也可以通过类似的机制诱导PCD。佛波酯阻断DNA片段化和细胞杀伤，表明蛋白激酶C的激活使细胞对PCD脱敏。因此，用诱导不平衡的持续Ca 2+增加的抗体靶向B-CLL细胞可能代表了破坏白血病细胞的合理策略。
Chronic lymphocytic leukemia of B cell type (B-CLL) is a neoplastic disorder characterized by the accumulation of small resting lymphocytes in the periphery. The phenotype of these cells suggests that they are "frozen" at an early stage of maturation. Glucocorticoid hormones are commonly used to treat patients with B-CLL, resulting in a reduction in the peripheral lymphocyte count by an undefined mechanism. Here we report that glucocorticoids stimulate DNA fragmentation characteristic of a suicide process known as apoptosis or programmed cell death (PCD) in suspensions of cells from patients with B-CLL. The effects can be mimicked by Ca2+ ionophore and involve a sustained increase in the cytosolic Ca2+ concentration. Specific antibodies binding to membrane-associated IgM on the leukemic cells can also induce PCD by a similar mechanism. Phorbol esters block DNA fragmentation and cell killing in response to all of the agents, suggesting that activation of protein kinase C desensitizes the cells to PCD. Targeting the B-CLL cells with antibodies that induce an unbalanced, sustained Ca2+ increase may therefore represent a rational strategy for the destruction of leukemic cells.