骨髓瘤硼替佐米耐药相关突变

1、MM硼替佐米相关突变2015-11-16pNRAS、KRASpPSMB5pNF-B通路持续活化相关pHSP:HSP90 HSP27方法方法：MassARRAY DNA质谱阵列质谱阵列基因分析基因分析uNRAS-MUT: 1、硼替佐米单药硼替佐米单药耐药相关耐药相关 2、PFS时间短时间短 3、不影响硼替佐米联合大剂量、不影响硼替佐米联合大剂量DEX方案化疗的患者的预后方案化疗的患者的预后uInterestingly, KRAS but not NRASmutation was significantly associated with TP53 mutation (15% of those w

2、ith KRAS mutation versus 3% of those without, P = 0.014).uwhen we analyzed the impact of KRAS and NRAS mutations on survival separately, only KRAS and not NRAS mutations were significantly associated with shorter overall survival and progression free survival.u体外实验体外实验：we here developed high levels

3、(45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib.lan Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the PSMB5 proteinla dramatic overexpression (up to

4、60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7,lhigh levels of cross-resistance to 5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugslno marked changes in chymotrypsin-like proteas

5、ome activity （类胰凝乳蛋白酶蛋白酶体）lrestoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing ofPSMB5 gene expression采用硼替佐米治疗，可诱导 SUDHL6(DHL6)淋巴瘤细胞凋亡，而在 SUDHL4(DHL4)淋巴瘤细胞中则无上述作用。微阵列分析显示 Hsp27 的 RNA 水平在 DHL4 淋巴瘤细胞中要高于 DHL6 细胞，从而相应的 Hsp27 蛋白表达水平也较高。采用反义(AS)修复策略阻断 Hsp27 后，可使 DHL4 淋巴瘤细胞在硼替佐米的作用下产生凋亡反应。野生型（WT）Hsp27 的异常表达可使硼替佐米敏感的 DHL6 细胞对硼替佐米产生耐药。硼替佐米耐药的 MM 患者的 MM 细胞 Hsp27 水平的高表达。Hsp27 可对线粒体核蛋白