多发性骨髓瘤
多发性骨髓瘤是第二常见的血液系统恶性肿瘤，也是最常累及骨骼的癌症。在多发性骨髓瘤中，癌变的浆细胞聚集在骨髓中，排挤健康的血细胞。癌细胞不是产生有益的抗体，而是产生可能导致并发症的异常蛋白质。
骨髓瘤是最常见的骨骼肿瘤，超过80%的骨髓瘤患者存在骨病 [1]。多发性骨髓瘤在临床和生物学上具有异质性，一些遗传改变被认为是骨髓瘤发生的驱动事件。二代测序显示，多发性骨髓瘤 [2]缺乏普遍的驱动突变。多发性骨髓瘤患者中出现的最常见突变是KRAS(23%的患者)、NRAS(20%)、FAM46C(11%)、DIS3(11%)和TP53(8%)。其他较少见但经常突变的基因包括BRAF, TRAF3, PRDM1, CYLD, RB1, IRF4, EGR1, MAX, HIST1H1E和ACTG1 [3-6]。
本文根据NCG(分析肿瘤基因的可重复性、同源性和网络特性)提供的信息，列出了与多发性骨髓瘤相关的部分蛋白。
本文介绍了参与多发性骨髓瘤发病机制的几个关键靶点，包括：
● ALOX12(花生四烯酸盐12-脂氧合酶，12S型)作用于不同的多不饱和脂肪酸底物，产生具有生物活性的脂质介质，包括二十碳烷和脂氧素。在炎症和氧化[7]中起重要作用。ALOX12的DNA异常甲基化和遗传变异与人类多种疾病和病理表型相关。ALOX12 rs1126667和rs434473与[8]治疗多发性骨髓瘤患者早期周围神经病变显著相关。
● 细胞周期蛋白D1 (CCND1)参与细胞周期的正常调节和肿瘤形成。融合、重排、错义突变、无义突变、沉默突变以及框内缺失和插入可在癌症中观察到。Eman M. sewiify等报道在多发性骨髓瘤 [9]患者中，cyclin D1基因扩增与疾病严重程度、不良预后以及MDR1表达增加相关。
● DIS3 (DIS3 Homolog, Exosome Endoribonuclease And 3'-5' Exoribonuclease)是一种与酵母蛋白Rrp44同源的RNA酶，可作为真核细胞细胞核内外泌体复合体的一部分。DIS3同时具有3'-5'核酸外切酶和核酸内切酶活性。DIS3是多发性骨髓瘤中最常见的突变基因之一，其突变热点与功能 [10]的变化一致。
● FAM46C (family with sequence similarity 46，成员C)是一种多聚A (A)聚合酶，与FAM46蛋白FAM46A、FAM46A和fam46d属于核苷酸转移酶超家族 [11]。它是多发性骨髓瘤中最常见的突变基因之一 [12]。FAM46C的功能丧失通过内质网反应转录物的不稳定驱动多发性骨髓瘤。FAM46C突变通过扰乱浆细胞分化和内质网稳态促进骨髓瘤发病和疾病进展。
● MAGED1（黑色素瘤相关抗原D1）是MAGE同源结构域（MHD）蛋白超家族的成员之一。MAGED1在发育和成年组织中普遍表达，但在大脑中特别丰富 [13]。Venkata D Yellapantula等人报道了使用全基因组测序和全外显子组测序初步鉴定的9个频繁突变基因列表，包括NRAS、KRAS、TP53、PNRC1、MAGED1、FAM46C、DIS3、CCND1和ALOX12B [14]。
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