IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)
IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)
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DOI：
10.1038/leu.2016.384
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发表时间：
2017-06-01
期刊：
影响因子：
11.4
通讯作者：
Langer, C.
中科院分区：
文献类型：
--
作者：
Kroenke, J.;Kuchenbauer, F.;Langer, C.
来那度胺是一种免疫调节化合物，在多发性骨髓瘤中具有较高的临床活性。来那度胺与Cereblon（CRBN）E3泛素连接酶的结合导致淋巴转录因子Ikaros（IKZF 1）和Aiolos（IKZF 3）的靶向泛素化和降解，从而抑制多发性骨髓瘤细胞的生长。最近，Basigin（BSG）被鉴定为另一种受CRBN调控的蛋白质，参与来那度胺的活性。在这里，我们分析了IKZF 1，IKZF 3，CRBN和BSG mRNA表达水平的预处理浆细胞的60例新诊断的多发性骨髓瘤患者在临床试验中统一治疗来那度胺联合强化化疗的预后价值。我们发现IKZF 1 mRNA表达水平与无进展生存期（PFS）显著相关。IKZF 1表达最低四分位数（Q1）患者的PFS上级其余四分位数患者（Q2-Q4; 3年PFS为86 vs 51%，P = 0.01）。这意味着总生存率显著提高（100 vs 74%，P = 0.03）。亚组分析显示，IKZF 1、IKZF 3和BSG表达水平对细胞遗传学定义的标准风险但非高风险患者的PFS有显著影响。我们的数据表明IKZF 1、IKZF 3和BSG表达水平在来那度胺治疗的多发性骨髓瘤中具有预后作用。
Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P = 0.01). This translated into a significant better overall survival (100 vs 74%, P = 0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.