Chng Wee J, Braggio Esteban, Mulligan George, Bryant Barbara, Remstein Ellen, Valdez Riccardo, Dogan Ahmet, Fonseca Rafael
Department of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA.
Blood. 2008 Feb 1;111(3):1603-9. doi: 10.1182/blood-2007-06-097774. Epub 2007 Nov 15.
Centrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression-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 II) or novel agents (bortezomib). Tumors with high CI 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 CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI 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.
中心体扩增在骨髓瘤中很常见，可能参与疾病的发病机制。我们之前得出了一种基于基因表达的中心体指数（CI），它与中心体扩增相关，并且在一小群接受异质性治疗的患者中是一个独立的预后因素。在本研究中，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，结果表明，无论患者是新诊断的还是复发的，无论接受强化治疗（总治疗方案II）还是新型药物（硼替佐米）治疗，高CI都是一个强有力的独立预后因素。高CI的肿瘤中，编码参与细胞周期、增殖、DNA损伤及G(2)-M检查点相关蛋白质的基因过表达，且与中心体和动粒/微管相关。特别是，极光激酶在高CI患者中显著过表达，蛋白质表达也相应增加。CI较高的人骨髓瘤细胞系对新型极光激酶抑制剂治疗更敏感。极光激酶可能是这些预后极差患者的新型治疗靶点。
