Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma
Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma
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DOI：
10.1182/blood-2014-02-557819
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发表时间：
2014-07-24
期刊：
影响因子：
20.3
通讯作者：
Stewart, A. Keith
中科院分区：
文献类型：
--
作者：
Zhu, Yuan Xiao;Braggio, Esteban;Stewart, A. Keith
Cereblon（CRBN）介导免疫调节药物（IMiD）在多发性骨髓瘤（MM）中的作用。使用2种不同的方法，我们鉴定了244种CRBN结合蛋白，并通过暴露于来那度胺后其丰度的变化确定了与MM生物学的相关性。最可再现地结合CRBN的蛋白质（>对照的四倍）包括DDB 1、CUL 4A、IKZF 1、KPNA 2、LTF、PFKL、PRKAR 2A、RANGAP 1和SHMT 2。来那度胺治疗后，46种CRBN结合蛋白的丰度降低。我们将注意力集中在其中的两个-IKZF 1和IKZF 3。IZKF表达在所有MM阶段或亚型中相似;然而，IKZF 1在5种IMiD耐药MM细胞系中的3种中显著较低。具有最低IKZF 1水平的细胞系（FR 4）还具有破坏性突变和上调IRF 4（IKZF靶点）的易位。在44例接受泊马度胺和地塞米松治疗的难治性MM患者中证实了CRBN结合蛋白的临床相关性，在这些患者中，IKZF 1基因低表达预测缺乏应答（最低表达四分位数中0/11应答）。CRBN、IKZF 1和KPNA 2水平也与总生存期的显著差异相关。我们的研究鉴定了CRBN结合蛋白，并证明除了CRBN，IKZF 1和KPNA 2外，表达可以预测生存结果。
Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes; however, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation and a translocation that upregulates IRF4, an IKZF target. Clinical relevance of CRBN-binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0/11 responses in the lowest expression quartile). CRBN, IKZF1, and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN-binding proteins and demonstrates that in addition to CRBN, IKZF1, and KPNA2, expression can predict survival outcomes.