Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Hum Pathol. 2012 Jun;43(6):858-64. doi: 10.1016/j.humpath.2011.07.013. Epub 2011 Nov 1.
Amplification of cyclin kinase subunit 1B gene on chromosome 1q21 resulting in overexpression of cyclin kinase subunit 1B has been associated with disease progression in multiple myeloma. Bortezomib is a proteasome inhibitor that induces apoptosis in various cancer cells and has been shown to be effective as a salvage therapy for relapsed/refractory multiple myeloma. Our group has recently reported the adverse effect of 1q21 gains in relapsed and refractory multiple myeloma treated with bortezomib. However, whether nuclear cyclin kinase subunit 1B protein expression correlates with 1q21 gains and has prognostic value in patients with multiple myeloma receiving bortezomib regimen remains unclear. We, therefore, evaluated the nuclear expression of cyclin kinase subunit 1B protein in patients with relapsed/refractory multiple myeloma undergoing bortezomib therapy by immunohistochemistry. The 1q21 amplification status of the same cohort was examined by interphase cytoplasmic immunoglobulin fluorescence in situ hybridization. Of 60 cases, 19 (32%) were positive for cyclin kinase subunit 1B nuclear expression by immunohistochemistry. Seventeen (89%) of the immunohistochemistry-positive cases had 1q21 gain detected by cytoplasmic immunoglobulin fluorescence in situ hybridization, and 17 (77%) of the 22 cases with 1q21 gain showed increased cyclin kinase subunit 1B protein expression. cyclin kinase subunit 1B expression and 1q21 gain were strongly correlated (P < .0001). There was no significant difference in response rate between patients with and without cyclin kinase subunit 1B nuclear expression. However, patients with cyclin kinase subunit 1B expression had a significantly shorter progression-free survival (1.9 versus 5.6 months; P < .0001) and overall survival (4.9 versus 22.4 months; P = .012) compared with those without cyclin kinase subunit 1B expression. Our results indicated that cyclin kinase subunit 1B nuclear expression detected by immunohistochemistry is an adverse prognostic factor for patients with multiple myeloma treated with bortezomib therapy.
1q21 上细胞周期蛋白激酶亚单位 1B 基因的扩增导致细胞周期蛋白激酶亚单位 1B 的过度表达与多发性骨髓瘤的疾病进展有关。硼替佐米是一种蛋白酶体抑制剂，可诱导多种癌细胞凋亡，并已被证明对复发性/难治性多发性骨髓瘤的挽救治疗有效。我们的研究小组最近报道了硼替佐米治疗复发性和难治性多发性骨髓瘤患者中 1q21 增益的不良影响。然而，核细胞周期蛋白激酶亚单位 1B 蛋白表达是否与 1q21 增益相关，并在接受硼替佐米方案治疗的多发性骨髓瘤患者中有预后价值尚不清楚。因此，我们通过免疫组织化学评估了接受硼替佐米治疗的复发性/难治性多发性骨髓瘤患者的核细胞周期蛋白激酶亚单位 1B 蛋白的表达。通过间期细胞质免疫球蛋白荧光原位杂交检测同一队列的 1q21 扩增状态。在 60 例病例中，19 例（32%）通过免疫组织化学检测到核细胞周期蛋白激酶亚单位 1B 呈阳性表达。免疫组织化学阳性病例中，17 例（89%）通过细胞质免疫球蛋白荧光原位杂交检测到 1q21 增益，22 例 1q21 增益病例中 17 例（77%）显示细胞周期蛋白激酶亚单位 1B 蛋白表达增加。细胞周期蛋白激酶亚单位 1B 表达与 1q21 增益呈强相关（P <.0001）。有核细胞周期蛋白激酶亚单位 1B 表达的患者与无核细胞周期蛋白激酶亚单位 1B 表达的患者之间的反应率无显著差异。然而，有细胞周期蛋白激酶亚单位 1B 表达的患者无进展生存期（1.9 个月与 5.6 个月；P <.0001）和总生存期（4.9 个月与 22.4 个月；P =.012）均显著短于无细胞周期蛋白激酶亚单位 1B 表达的患者。我们的结果表明，免疫组织化学检测到的核细胞周期蛋白激酶亚单位 1B 表达是接受硼替佐米治疗的多发性骨髓瘤患者的不良预后因素。
