骨髓瘤硼替佐米耐藥相關(guān)突變

1、MM硼替佐米相關(guān)突變2015-11-16pNRAS、KRASpPSMB5pNF-B通路持續(xù)活化相關(guān)pHSP:HSP90 HSP27方法方法：MassARRAY DNA質(zhì)譜陣列質(zhì)譜陣列基因分析基因分析uNRAS-MUT: 1、硼替佐米單藥硼替佐米單藥耐藥相關(guān)耐藥相關(guān) 2、PFS時(shí)間短時(shí)間短 3、不影響硼替佐米聯(lián)合大劑量、不影響硼替佐米聯(lián)合大劑量DEX方案化療的患者的預(yù)后方案化療的患者的預(yù)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體外實(shí)驗(yàn)體外實(shí)驗(yàn)：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 （類(lèi)胰凝乳蛋白酶蛋白酶體）lrestoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing ofPSMB5 gene expression采用硼替佐米治療，可誘導(dǎo) SUDHL6(DHL6)淋巴瘤細(xì)胞凋亡，而在 SUDHL4(DHL4)淋巴瘤細(xì)胞中則無(wú)上述作用。微陣列分析顯示 Hsp27 的 RNA 水平在 DHL4 淋巴瘤細(xì)胞中要高于 DHL6 細(xì)胞，從而相應(yīng)的 Hsp27 蛋白表達(dá)水平也較高。采用反義(AS)修復(fù)策略阻斷 Hsp27 后，可使 DHL4 淋巴瘤細(xì)胞在硼替佐米的作用下產(chǎn)生凋亡反應(yīng)。野生型（WT）Hsp27 的異常表達(dá)可使硼替佐米敏感的 DHL6 細(xì)胞對(duì)硼替佐米產(chǎn)生耐藥。硼替佐米耐藥的 MM 患者的 MM 細(xì)胞 Hsp27 水平的高表達(dá)。Hsp27 可對(duì)線(xiàn)粒體核蛋白