Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.
Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.
复制标题
DOI：
10.1371/journal.pone.0007768
复制
发表时间：
2009-11-05
期刊：
影响因子：
3.7
通讯作者：
Neubauer A
中科院分区：
文献类型：
--
作者：
Meyer M;Rübsamen D;Slany R;Illmer T;Stabla K;Roth P;Stiewe T;Eilers M;Neubauer A
急性髓系白血病（AML）是一种起源于具有异质遗传背景的髓系祖细胞的克隆性疾病。大剂量阿糖胞苷用作标准巩固化疗。致癌 RAS 突变在 AML 中经常观察到，并且与阿糖胞苷的有益反应相关。为什么患有致癌 RAS 的 AML 患者从高剂量阿糖胞苷缓解后治疗中获益最多，目前尚不清楚。在这里，我们使用表达条件性 MLL-ENL-ER 致癌基因的骨髓细胞来研究致癌 RAS 和化疗药物的相互作用。我们发现，致癌 RAS 与阿糖胞苷等细胞毒性药物协同作用，激活 DNA 损伤检查点，从而产生 p53 依赖性遗传程序，减少克隆形成并增加骨髓分化。我们的数据可以解释对患有致癌 RAS 的 AML 患者用较高剂量的阿糖胞苷治疗所观察到的有益效果，并表明诱导 p53 依赖性分化，例如诱导 p53 依赖性分化。通过干扰 Mdm2 介导的降解，可能是提高化疗治愈率的合理方法。这些数据还支持这样的观点：细胞毒性药物的治疗成功可能取决于它们促进肿瘤起始细胞分化的能力。
Acute myeloid leukemia (AML) is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and are associated with beneficial response to cytarabine. Why AML-patients with oncogenic RAS benefit most from high-dose cytarabine post-remission therapy is not well understood. Here we used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higher dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
2.6
作者：
Darley, RL;Burnett, AK
通讯作者：
Burnett, AK
影响因子：
11.5
作者：
Illmer, T;Thiede, C;Schaich, M
通讯作者：
Schaich, M