Protein regulation in multiple myeloma

我们小组最近发表的一篇文章表明，诱导编码SUMOylation通路效应子的基因与MM患者生存率降低相关。初步数据表明，来自该途径的基因不仅与复发性MM患者对硼替佐米的反应相关，而且在初次诊断时定义了一部分患者。因此，我们寻求进一步研究SUMOylation途径在骨髓瘤形成中的蛋白调控作用。特异性目的1：探讨选择性E3s基因表达是否在MM患者样本中被诱导，并与对硼替佐米治疗的耐药相关。我们将检查CREST和APEX临床试验患者的基因表达谱。初步数据表明，与正常浆细胞相比，RNF4在MM恶性浆细胞中的表达明显更高，RNF4是一种识别多sumoylated蛋白进行蛋白酶体降解的E3。此外，在对硼替佐米无反应的MM患者中，RNF4和sumo化、泛素化和蛋白酶体途径的其他组分可能被诱导。我们将进一步探究RNF4在MM细胞系中蛋白调控和对硼替佐米的抗性中的作用。具体来说，我们将在MM细胞系中过表达和敲低RNF4，并检测硼替佐米治疗的细胞效应。具体目标2：将生物标志物谱扩展到SUMO、Ubiqutin和蛋白酶体亚基家族的基因，以便更好地识别更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。我们将包括来自每个功能相关基因家族的至少10个基因，并将其与临床参数（如年龄、b2微球蛋白、c反应蛋白和白蛋白）的预测值进行比较。我们还将研究硼替佐米治疗后个体与总生存率的相关性。我们还将在实验室中产生耐硼替佐米MM细胞系，并量化这些基因在耐药细胞系中与亲本硼替佐米敏感细胞系的表达。

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.