A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia
A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia
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DOI：
10.1158/0008-5472.can-09-2604
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
--
作者：
Loeder, Sandra;Zenz, Thorsten;Fulda, Simone
逃避细胞凋亡是慢性淋巴细胞白血病（CLL）的一个特征，需要新的策略来绕过耐药性。在这里，我们提供了第一个证据，证明小分子x连接的凋亡抑制剂（XIAP）抑制剂与死亡受体配体和肿瘤坏死因子相关的凋亡诱导配体（TRAIL）联合为CLL（包括耐药疾病或预后不良的亚群）提供了一种触发细胞凋亡的新途径。XIAP、细胞LAP (cIAP) 1和cIAP2在原发性CLL样本中高水平表达。CLL细胞系的概念验证研究表明，亚毒性浓度的XIAP抑制剂显著增强trail诱导的细胞凋亡，并对cd95介导的细胞凋亡增敏。同样重要的是，在原发性CLL样本中，XIAP抑制剂与TRAIL协同作用，在27例（67%）病例中有18例触发细胞凋亡。这种XIAP抑制剂诱导和trail诱导的细胞凋亡涉及caspase-3激活，并被caspase抑制剂zVAD.fmk阻断。XIAP抑制剂和TRAIL的协同相互作用甚至在具有不良预后特征（即17p缺失、TP53突变、化疗难治性疾病或V-H基因未突变）的不同亚组患者中也很明显。有趣的是，与V-H基因突变的样本相比，未突变V-H基因的病例对XIAP抑制剂诱导和trail诱导的细胞凋亡明显更敏感，这表明b细胞受体信号在细胞凋亡调控中的作用。通过表明XIAP抑制剂联合TRAIL提供了一种新的策略，即使在耐药形式和预后不良的CLL亚组中也能触发细胞凋亡，我们的研究结果对CLL中基于细胞凋亡的治疗的发展具有重要意义。[癌症研究2009；69 (23): 8977 - 86)
Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular LAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V-H genes). Interestingly, cases with unmutated V-H genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V-H gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL. [Cancer Res 2009;69(23):8977-86]