Protein regulation in multiple myeloma

我们小组最近发表的一篇论文表明，编码SUMO化途径效应器的基因的诱导与多发性骨髓瘤患者生存率的降低有关。初步数据表明，这一途径的基因不仅与复发性多发性骨髓瘤患者对硼替佐米的反应有关，而且还定义了初诊时的患者亚群。因此，我们试图进一步研究蛋白SUMO化途径在骨髓增生症中的调节作用。特异性目的1：探讨选择性E3基因在多发性骨髓瘤患者样本中的表达是否与其耐药有关。我们将检查CREST和APEX临床试验中患者产生的基因表达谱。初步数据表明，RNF4是一种识别多聚糖基化蛋白降解蛋白酶体的E3，在MM恶性浆细胞中的表达明显高于正常浆细胞。此外，在对硼替佐米无效的多发性骨髓瘤患者中，可能会诱导RNF4和SUMO化、泛素化和蛋白酶体途径的其他组成部分。我们将进一步探讨RNF4在多发性骨髓瘤细胞系的蛋白调控和对Bortezomib耐药中的作用。具体地说，我们将在MM细胞系中过表达和敲除RNF4，并检查Bortezomib治疗的细胞效应。特定目的2：将生物标记物的图谱扩展到相扑、泛素和蛋白酶体亚单位家族中的基因，以便更好地识别更有可能对蛋白酶体定向治疗有反应的患者亚群，并确定治疗干预的新靶点。我们将包括每个功能相关基因家族中的至少10个基因，并将它们的预测价值与临床参数如年龄、B2-微球蛋白、C-反应蛋白和白蛋白的预测价值进行比较。我们还将调查波特佐米治疗后个体与总存活率的相关性。我们还将在实验室中建立耐药的MM细胞系，并将这些基因在耐药细胞系中的表达与亲本的Bortezomib敏感细胞系进行比较。

A recent publication from our group demonstrated that the induction of genes encoding effectors of the SUMOylation pathway correlated with decreased MM patient survival. Preliminary data suggest that genes from this pathway not only correlate with response to bortezomib in patients with relapsed MM, but also define a subset of patients at initial diagnosis. Therefore, we seek to further investigate the role of protein regulation by the SUMOylation pathway in myelomagenesis. SPECIFIC AIM 1: to investigate whether gene expression of selective E3s are induced in MM patient samples and correlated with resistance to bortezomib-based therapy. We will examine the gene expression profiles generated from patients on the CREST and APEX clinical trials. Preliminary data suggests that RNF4, an E3 that recognizes poly-SUMOylated proteins for proteasomal degradation, is significantly more highly expressed in MM malignant plasma cells compared to normal plasma cells. Moreover, RNF4 and other components of the SUMOylation, Ubiquitination and Proteasome pathways may be induced in MM patients that did not respond to bortezomib. We will further interrogate the role of RNF4 in protein regulation and resistance to bortezomib in MM cell lines. Specifically, we will both over-express and knock down RNF4 in MM cell lines and examine the cellular effects of treatment with bortezomib. SPECIFIC AIM 2: to expand the biomarker profiles to genes in the SUMO, Ubiqutin and proteasome subunit families in order to better identify subpopulations of patients more likely to respond to proteasome-directed therapy and identify new targets for therapeutic intervention. We will include at least 10 genes from each family of functionally related genes and compare their predictive values to that of clinical parameters such as age, B2-microglobulin, C-reactive protein and albumin. We will also investigate the individual correlations with overall survival after bortezomib treatment. We will also generate bortezomib-resistant MM cell lines in the laboratory and quantify the expression of these genes in the resistant cell lines compared to the parental bortezomib-sensitive cell lines.