The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition
The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition
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DOI：
10.1182/blood-2007-06-097774
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Fonseca, Rafael
中科院分区：
文献类型：
--
作者：
Chng, Wee J.;Braggio, Esteban;Fonseca, Rafael
中心体扩增在骨髓瘤中很常见，可能参与疾病的发病机制。我们以前已经推导出一个基于基因表达的中心体指数（CI），与中心体扩增相关，是一个独立的预后因素，在一个小队列的异质性治疗的患者。在这项研究中，我们在进入临床试验的2个大型患者队列中验证了CI的预后意义，并表明高CI是新诊断和复发患者的一个强大的独立预后因素，无论是接受强化治疗（总治疗11）还是新型药物（硼替佐米）。具有高Cl过表达基因的肿瘤，这些基因编码参与细胞周期、增殖、DNA损伤和G（2）-M检查点的蛋白质，并与中心体和动粒/微管相关。特别是，极光激酶显着过表达的患者高氯，与一致的蛋白质表达增加。具有较高Cl的人骨髓瘤细胞系对用新型极光激酶抑制剂治疗更敏感。Aurora激酶可能是这些预后极差患者的新治疗靶点。
Centrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene express ion-based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy 11) or novel agents (bortezomib). Tumors with high Cl overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G(2)-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high Cl, with concordant increase in protein expression. Human myeloma cell lines with higher Cl are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.