Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109-0936, USA.
Blood. 2010 Jul 8;116(1):71-80. doi: 10.1182/blood-2010-01-261628. Epub 2010 Apr 19.
The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small ( approximately 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.
大多数急性髓细胞白血病（AML）患者的生存率仍然较差，需要新的治疗方法来改善预后。鉴于突变型 p53 的 AML 比例较小（约 10%），因此研究 MDM2 抑制剂作为 AML 的治疗方法似乎是合理的。在这里，我们报告了对 109 例 AML blasts 进行体外敏感性和耐药性的详细特征分析结果，使用了 MDM2 抑制剂 MI219。与之前的观察结果一致，所有突变型 p53 的 AML 病例均对 MI219 耐药。重要的是，约 30%的野生型 p53 的 AML 病例也表现出对 MI219 的原发性耐药。对具有野生型 p53 的 AML blasts 中与 MI219 耐药相关的潜在机制的分析揭示了明显的分子缺陷，包括 MDM2 抑制剂或外照射治疗后 p53 蛋白诱导降低或缺失。此外，耐药性blasts 的另一个亚群在 MI219 治疗后显示出强大的 p53 蛋白诱导，表明 p53 蛋白功能缺陷或凋亡 p53 网络缺陷。最后，对非常敏感的 AML 病例的分析发现与突变型 Flt3 状态（Flt3-ITD）之间存在强烈且显著的关联，这首次确定了一个具有临床高风险的 AML 群体，可能特别受益于 MDM2 抑制剂治疗。
