Opel Daniela, Schnaiter Andrea, Dodier Dagmar, Jovanovic Marjana, Gerhardinger Andreas, Idler Irina, Mertens Daniel, Bullinger Lars, Stilgenbauer Stephan, Fulda Simone
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
Institute for Experimental Cancer Research in Pediatrics, , Goethe University, Frankfurt, Germany.
Int J Cancer. 2015 Dec 15;137(12):2959-70. doi: 10.1002/ijc.29650. Epub 2015 Jul 31.
Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-κB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-κB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)α, as zVAD.fmk, necrostatin-1 or TNFα-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.
凋亡抑制蛋白（IAP）在慢性淋巴细胞白血病（CLL）细胞中高表达，有助于逃避细胞死亡并导致治疗反应不佳。在此，我们报告Smac模拟物BV6在51个研究的CLL样本中的28个（54%）中剂量依赖性地诱导细胞死亡，而健康供体的B细胞基本不受影响。重要的是，BV6在预后不良的病例中，例如具有未突变的VH状态和TP53突变的病例中，比预后未知或良好的样本显著更有效。大多数17p缺失的病例（10/12）和氟达拉滨难治性病例对BV6有反应，表明BV6的作用独立于p53。BV6在模拟微环境的生存条件下也能触发细胞死亡，例如通过添加CD40配体或条件培养基。基因表达谱分析确定细胞死亡、NF-κB和氧化还原信号是BV6调节的主要通路，不仅在CLL中如此，在核心结合因子（CBF）急性髓性白血病（AML）中也是如此。一致地，BV6刺激活性氧（ROS）的产生，这有助于BV6诱导的细胞死亡，因为抗氧化剂可减少细胞死亡。虽然BV6在原发性CLL样本中导致细胞凋亡抑制蛋白（cIAP）1和cIAP2的降解以及核因子-κB（NF-κB）通路的激活，但BV6诱导细胞死亡独立于半胱天冬酶活性、受体相互作用蛋白（RIP）1活性或肿瘤坏死因子（TNF）α，因为zVAD.fmk、坏死抑制因子-1或TNFα阻断抗体恩利均不能抑制细胞死亡。总之，这些关于BV6调节CLL细胞死亡的新见解对于开发新的治疗策略以克服细胞死亡抗性具有重要意义，特别是在预后不良的CLL亚组中。
