Department of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Leuk Lymphoma. 2013 Aug;54(8):1840-3. doi: 10.3109/10428194.2013.796056. Epub 2013 Jul 1.
The prognostic role of ATM defects is well documented in chronic lymphocytic leukemia. However, the predictive value of ATM inactivation is much less understood, even in response to common drugs like fludarabine. It has been demonstrated that CLL cells having inactive ATM exhibit defective phosphorylation of its downstream targets after fludarabine treatment. We performed alternative analysis focusing on fludarabine-induced p53 accumulation and induction of p53-downstream genes after artificial ATM inhibition and, in parallel, using cells with endogenous ATM inactivation. We show that after 24h fludarabine exposure: (i) 5 out of 8 ATM-deficient samples (63%) normally accumulated p53 protein, and (ii) all analyzed ATM-deficient samples (n = 7) manifested clear induction of p21, PUMA, BAX, and GADD45 genes. In all experiments, doxorubicin was used as a confined ATM inductor and confirmed effective ATM inactivation. In conclusion, CLL cells lacking functional ATM appear to have normal response to fludarabine regarding the p53 pathway activation.
ATM 缺陷在慢性淋巴细胞白血病中的预后作用已有充分的文献记载。然而，ATM 失活的预测价值则知之甚少，即使是针对常见的药物，如氟达拉滨。已经证明，在氟达拉滨治疗后，ATM 失活的 CLL 细胞表现出其下游靶标的磷酸化缺陷。我们进行了替代分析，重点关注人工抑制 ATM 后氟达拉滨诱导的 p53 积累和 p53 下游基因的诱导，并平行使用内源性 ATM 失活的细胞。我们发现，在氟达拉滨暴露 24 小时后：（i）8 个 ATM 缺陷样本中有 5 个（63%）正常积累 p53 蛋白，（ii）所有分析的 ATM 缺陷样本（n=7）均明显诱导了 p21、PUMA、BAX 和 GADD45 基因。在所有实验中，阿霉素被用作局限的 ATM 诱导剂，并证实了有效的 ATM 失活。总之，缺乏功能 ATM 的 CLL 细胞在 p53 途径激活方面对氟达拉滨似乎有正常的反应。
