Lueck Sonja C, Russ Annika C, Botzenhardt Ursula, Schlenk Richard F, Zobel Kerry, Deshayes Kurt, Vucic Domagoj, Döhner Hartmut, Döhner Konstanze, Fulda Simone, Bullinger Lars
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA.
Oncotarget. 2016 Aug 2;7(31):49539-49551. doi: 10.18632/oncotarget.10390.
Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
细胞凋亡在大多数（即便不是所有）癌症中都存在失调现象，包括血液系统恶性肿瘤。迄今为止，拮抗凋亡抑制蛋白（IAP）的Smac模拟物主要在急性髓系白血病（AML）细胞系中进行了研究；然而，对于Smac模拟物在原发性AML样本中的治疗潜力仍知之甚少。因此，在本研究中，我们调查了Smac模拟物BV6在67例成年AML患者诊断样本中的抗白血病活性，并将反应与临床、细胞遗传学和分子标志物以及基因表达谱相关联。使用阿糖胞苷（ara-C）治疗作为标准化疗药物。有趣的是，约一半（51%）的原发性AML样本对BV6敏感，21%为中度反应，而28%耐药。值得注意的是，69%对ara-C耐药的样本对BV6显示出良好至中等的反应。此外，ara-C与BV6联合治疗在大多数样本中发挥相加作用。全基因组基因表达谱分析确定细胞死亡、TNFR1和NF-κB信号通路是BV6在敏感但非耐药病例中激活的主要通路。此外，原发性AML原始细胞对BV6的敏感性与诊断样本中TNF表达水平显著升高、XIAP水平降低以及NPM1突变相关。在大量原发性AML样本中，这些数据为调节AML中Smac模拟物反应的因素提供了新的见解，并对基于Smac模拟物的AML治疗及相关诊断的发展具有重要意义。
