Cereblon基因表达水平与来那度胺治疗POEMS综合征疗效的相关性研究

发布时间：2018-07-10 03:14

本文选题：POEMS综合征 + 来那度胺　；参考：《北京协和医学院》2015年博士论文

【摘要】：背景及目的：POEMS综合征是一种高致残性的克隆性浆细胞病,尚无标准治疗。近年来,来那度胺在治疗POEMS综合征方面取得了较好的疗效,但个体间差异较大,一部分患者可以获得完全缓解,而另一部分患者则无效。既往针对多发性骨髓瘤的研究已经证实cereblon (CRBN)是来那度胺作用的直接靶点分子,cereblon基因高表达的患者往往具有更好的药物敏感性及疗效。同时研究还发现cereblon下游靶基因IKZF1和IKZF3在来那度胺抗骨髓瘤方面也起到了重要作用。但在对不伴5q-的骨髓增生异常综合征患者的研究中并未发现cereblon基因表达水平与来那度胺疗效的相关性,提示来那度胺在不同疾病的治疗中可能存在不同的作用机制。目前尚无关于cereblon基因表达水平与来那度胺治疗POEMS综合征疗效相关性的研究。因此,本研究拟通过比较来那度胺治疗有效组和无效组POEMS综合征患者的骨髓浆细胞中基线cereblon、IKZF1、 IKZF3基因的mRNA及蛋白表达水平的差异,揭示出上述基因及蛋白与来那度胺治疗POEMS综合征疗效的相关性。方法：通过对入组临床试验(一项单中心、开放性II期临床试验：评价来那度胺联合地塞米松方案治疗初治POEMS综合征患者的有效性和安全性)的初治POEMS综合征患者进行基线数据采集和随访,评价来那度胺治疗POEMS综合征的有效性、安全性及预后分析。收集北京协和医院自2014年3月至2015年4月期间确诊为POEMS综合征的患者骨髓液和骨髓活检组织,CD138免疫磁珠分选得到纯化的CD138+浆细胞,采用real-time PCR的方法检测所有患者CD138+浆细胞中cereblon, IKZF1, IKZF3基因的mRNA表达水平；采用连续切片免疫组化法检测骨髓活检组织的浆细胞中上述基因蛋白产物的水平。通过比较来那度胺治疗有效组与无效组之间上述基因及蛋白表达的差异来探索上述基因及蛋白与来那度胺治疗疗效的相关性。结果：临床试验共入组41例初治POEMS综合征患者,中位总体神经功能限制评分(ONLS)为4分(1-10分),所有患者均接受来那度胺联合地塞米松方案的治疗。在中位随访时间10个月(2-14个月)后,血液学、神经症状、血清VEGF水平、和临床水负荷的总有效率分别达70%、90.2%、77.5%、和100%。治疗期间无1例药物相关死亡,仅1例患者出现3级皮疹。2例(4.9%)患者在治疗期间因疾病进展而死亡,另1例(2.5%)因疾病进展转行自体干细胞移植。1年疾病无进展生存(PFS)和疾病总生存(OS)分别为92.7%和95.1%。治疗有效组和无效组POEMS综合征患者其1年PFS分别为100%和62.5%(p=0.0006)；1年OS分别为100%和73%(p=0.0055)。我们通过进一步的研究发现,治疗有效的POEMS综合征患者骨髓浆细胞中的基线cereblon基因的平均nRNA表达水平为2.51%,无效组为0.44%(P=0.005)。两组IKZF1基因的表达分别为1.51%和0.18%(p=0.002)；IKZF3基因的平均表达水平为2.07%和0.51%(p=0.076)。在蛋白层面上,我们仅发现cereblon蛋白产物(CRBN)与来那度胺疗效相关(p=0.029)。此外,我们还发现IKZF1基因的mRNA表达水平与疾病预后密切相关,IKZF1低表达的患者具有更短的PFS(p= 0.02),临床预后较差,但其对OS并无影响。结论：来那度胺对初治POEMS综合征具有很好的疗效,但是存在较大的个体差异,而患者骨髓CD138+浆细胞中基线cereblon, IKZF1的mRNA表达水平与来那度胺的疗效密切相关,上述基因高表达的患者具有更好的药物疗效；此外研究还发现IKZF1基因高表达的患者具有更长的PFS。
[Abstract]:Background and purpose: POEMS syndrome is a highly crippled cloned plasma cell disease. There is no standard treatment yet. In recent years, amido has achieved good results in the treatment of POEMS syndrome, but there is a large difference among individuals, some patients can get complete remission, and the other part of the patients are invalid. The study has confirmed that cereblon (CRBN) is a direct target molecule to the action of amines. The patients with high expression of cereblon gene often have better drug sensitivity and efficacy. Meanwhile, the study also found that the downstream target gene of cereblon, IKZF1 and IKZF3, also plays an important role in the anti myeloma of the amines, but in the bone marrow that does not accompany 5q-. In the study of patients with hyperplastic syndrome, there was no correlation between the cereblon gene expression level and the effect of amido, suggesting that amines may have different mechanisms of action in the treatment of different diseases. There is no study on the correlation between the expression level of cereblon gene and the effect of the treatment of POEMS syndrome on the treatment with amido. This study is to compare the differences in the mRNA and protein expression levels of the baseline cereblon, IKZF1, and IKZF3 genes in the myeloma cells of the effective and ineffective group POEMS syndrome, and to reveal the correlation between the gene and protein and the therapeutic effect of nalamines on the treatment of POEMS syndrome. (a single center, open II phase clinical trial: baseline data collection and follow-up for patients with primary POEMS syndrome treated with amidomide combined with dexamethasone regimen for patients with initial POEMS syndrome) to evaluate the efficacy, safety, and prognosis of the amines in the treatment of POEMS syndrome. Collection of Beijing Association The bone marrow fluid and bone marrow biopsy tissue of the patients with POEMS syndrome from March 2014 to April 2015 were selected and the purified CD138+ plasma cells were separated by CD138 immunomagnetic beads. The expression level of cereblon, IKZF1, IKZF3 gene in CD138+ plasma cells in all patients was detected by real-time PCR; continuous slice immunization was used. The level of the above gene protein products in the plasma cells of bone marrow biopsy tissue was detected by histochemical method. The correlation between the gene and protein expression of the above gene and protein was explored by comparing the difference of the expression of the above gene and protein between the effective group and the ineffective group. Results: 41 cases of POEMS synthesis in the clinical trial group were enrolled. The total median nerve function limit score (ONLS) was 4 (1-10). All patients received treatment with amido combined with dexamethasone. After a median follow-up period of 10 months (2-14 months), the total effective rate of Hematology, neurologic, serum VEGF, and clinical water load was 70%, 90.2%, 77.5%, and 100%., respectively. No 1 cases of drug-related death were found, only 1 patients had 3 rash.2 cases (4.9%) in.2 cases (4.9%), and 1 (2.5%) underwent autologous stem cell transplantation for.1 years of disease progression free survival (PFS) and disease total survival (OS), 92.7% and 95.1%., respectively, and the 1 year PF in the ineffective group of patients with POEMS syndrome. S was 100% and 62.5% (p=0.0006), and 1 years OS were 100% and 73% (p=0.0055). We found that the average nRNA expression level of the baseline cereblon gene in the myeloelt cells of the patients with effective POEMS syndrome was 2.51%, and the ineffective group was 0.44% (P= 0.005). The expression of the IKZF1 gene in the two group was 1.51% and 0.18% (p=0.0), respectively. 02); the average expression level of the IKZF3 gene was 2.07% and 0.51% (p=0.076). At the protein level, we only found that the cereblon protein product (CRBN) was associated with the therapeutic effect of amido (p=0.029). In addition, we also found that the mRNA expression of the IKZF1 gene was closely related to the prognosis of the disease, and the patients with low expression of IKZF1 had a shorter PFS (p= 0.02), and the clinical value of IKZF1 was shorter (p= 0.02). The prognosis is poor, but it has no effect on OS. Conclusion: amido has a good effect on the initial treatment of POEMS syndrome, but there is a large individual difference, while the baseline cereblon in the CD138+ plasma cell of the patient's bone marrow, the mRNA expression level of IKZF1 is closely related to the effect of the amines, and the above gene is better for the patients with the high expression of the gene. In addition, the study also found that patients with high IKZF1 expression had longer PFS..
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R597

【共引文献】