Tumor necrosis factor-related apoptosis-inducing ligand and the regulation of hematopoiesis
Tumor necrosis factor-related apoptosis-inducing ligand and the regulation of hematopoiesis
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DOI：
10.1097/moh.0b013e3282f15fa6
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Zauli, Giorgio
中科院分区：
文献类型：
--
作者：
Secchiero, Paola;Zauli, Giorgio
本文将重点介绍肿瘤坏死因子相关凋亡诱导配体(TRAIL)/TRAIL-受体在造血病理生理中的新作用，以及重组TRAIL或抗TRAIL- r1 /-R2激动抗体在血液系统恶性肿瘤治疗中的潜在治疗应用。虽然CD34（+）干细胞/祖细胞不表达TRAIL-受体，并且受到TRAIL诱导的细胞凋亡的保护，但越来越多的证据表明，在再生障碍性贫血、范可尼贫血和骨髓增生异常综合征的病理生理中，骨髓水平上TRAIL的表达/释放升高起着重要作用。体外数据显示重组TRAIL与蛋白酶体或组蛋白去乙酰化酶抑制剂、天然化合物或小分子在治疗髓系和淋巴系恶性肿瘤中的协同作用。此外，尽管重组TRAIL和抗TRAIL- r1 /-R2抗体在体内都具有良好的耐受性，但抗TRAIL- r1 /-R2激动性抗体显示出避免可溶性受体骨保护素中和活性的潜在优势。虽然骨髓水平上TRAIL的慢性病理性升高可能导致正常造血功能受损，但重组TRAIL和抗TRAIL- r1 /-R2激动抗体的使用对于血液恶性肿瘤特别是多发性骨髓瘤的治疗尤其有希望，特别是如果与创新治疗化合物联合使用。
Purpose of reviewThis review will focus on the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptors in the pathophysiology of hematopoiesis and on the potential therapeutic applications of either recombinant TRAIL or anti-TRAIL-R1/-R2 agonistic antibodies for the treatment of hematological malignancies.Recent findingsWhile CD34(+) stem/progenitor cells do not express TRAIL-receptors and are protected from TRAIL-induced apoptosis, accumulating evidence points to a role for elevated expression/release of TRAIL at the bone marrow level in the pathophysiology of aplastic anemia, Fanconi anemia, and myelodysplastic syndromes. In-vitro data show promising synergistic effects of recombinant TRAIL in association with proteasome or histone deacetylase inhibitors, natural compounds or small molecules in the therapy of myeloid and lymphoid malignancies. Moreover, although both recombinant TRAIL and anti-TRAIL-R1/-R2 antibodies are well tolerated in vivo, anti-TRAL-R1/-R2 agonistic antibodies show the potential advantage of avoiding the neutralizing activity of the soluble receptor osteoprotegerin.SummaryWhile a chronic pathological elevation of TRAIL at the bone marrow level might contribute to the impairment of normal hematopoiesis, the use of recombinant TRAIL and anti-TRAIL-R1/-R2 agonistic antibodies appears particularly promising for the treatment of hematological malignancies in particular, of multiple myeloma, especially if used in association with innovative therapeutic compounds.