Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia
Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia
复制标题
Smac 模拟物靶向凋亡蛋白抑制剂可在慢性淋巴细胞白血病预后不良的亚组中引发细胞死亡
DOI：
10.1002/ijc.29650
复制
发表时间：
2015
影响因子：
6.4
通讯作者：
Fulda S.
中科院分区：
文献类型：
--
作者：
Opel D;Schnaiter A;Dodier D;Jovanovic M;Gerhardinger A;Idler I;Mertens D;Bullinger L;Stilgenbauer S;Fulda S.
凋亡抑制剂（IAP）蛋白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和不良的治疗反应。在这里，我们报告了Smac模拟BV6剂量依赖性诱导51个CLL样本中的28个（54%）细胞死亡，而来自健康供体的B细胞基本上不受影响。重要的是，BV6在预后不利的情况下更有效，例如：非突变的VH状态和TP53突变比预后未知或良好的样本要好。大多数17p缺失病例（10/12）和氟达拉滨难治性病例对BV6有应答，表明BV6独立于p53起作用。BV6还会在模拟微环境的生存条件下引发细胞死亡，例如：加入CD40配体或条件培养基。基因表达谱鉴定了CLL和核心结合因子（CBF）急性髓系白血病（AML）中BV6调控的细胞死亡、NF - κB和氧化还原信号通路。一直以来，BV6刺激活性氧（ROS）的产生，这有助于BV6诱导的细胞死亡，因为抗氧化剂可以减少细胞死亡。虽然BV6在原发性CLL样品中导致细胞凋亡抑制剂（cIAP）1和cIAP2的降解和核因子κB （NF - κB）途径的激活，但BV6诱导细胞死亡独立于caspase活性、受体相互作用蛋白（RIP）1活性或肿瘤坏死因子(TNF)α，如zVAD。fmk、necrostatin - 1或TNFα阻断抗体Enbrel均不能抑制细胞死亡。总之，这些关于BV6调节的CLL细胞死亡的新见解对于开发新的治疗策略来克服细胞死亡抵抗具有重要意义，特别是在预后不良的CLL亚组中。
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.
登录
查看更多内容
影响因子：
13.8
作者：
Vandenabeele, Peter;Declercq, Wim;Vanden Berghe, Tom
通讯作者：
Vanden Berghe, Tom
影响因子：
9
作者：
通讯作者：
--
影响因子：
9
作者：
通讯作者：
--
影响因子：
20.3
作者：
Zenz, Thorsten;Kroeber, Alexander;Stilgenbauer, Stephan
通讯作者：
Stilgenbauer, Stephan
影响因子：
50.3
作者：
Petersen, Sean L.;Wang, Lai;Wang, Xiaodong
通讯作者：
Wang, Xiaodong