Molecular Pathogenesis of Multiple Myeloma

我们将继续提高对MGUS发病机制的认识， 骨髓瘤，如下所述。首先，在最近一项尚未发表的研究中，我们已经确定， 30例多发性骨髓瘤中有27例之前有MGUS肿瘤，这提供了一些 首次有证据表明新发多发性骨髓瘤并不常见。值得注意的是，在四个（13%） 在这些患者中，多发性骨髓瘤和先前的MGUS肿瘤仅为轻链，或 无分泌。第二，我们已经确定了七个主要的易位伴侣， 存在于40%的多发性骨髓瘤肿瘤中并包含三个易位组：细胞周期蛋白D， MAF和MMSET/FGFR 3。第三，我们确定细胞周期蛋白D基因的失调是一种细胞周期蛋白的异常表达。 MGUS和多发性骨髓瘤的早期统一事件。第四，这两个早期致癌 事件使我们能够提出TC（易位/细胞周期蛋白D）分类，这似乎 适用于所有MGUS和多发性骨髓瘤肿瘤，但也已被证明具有 对治疗决策的重要性。第五，我们已经确定， 参与肿瘤进展的易位具有结构特征， 染色体伴侣，以区别于原发性易位。第六，我们有 确定了通过外源性配体或通过至少九个突变的NF κ B活化， NF κ B途径的组分对于正常血浆的存活和生长是重要的。 细胞以及大多数MGUS和MM肿瘤。这表明MGUS和MM肿瘤可能是 成瘾于该途径，因此对抑制NF κ B途径的药物敏感。第七、 我们已经确定N-RAS突变在表达细胞周期蛋白的肿瘤中更为普遍， D1（22%）比表达细胞周期蛋白D2（4%）的肿瘤，而K-RAS突变具有相同的 两种肿瘤的患病率均为17%。虽然我们目前还不了解这种RAS 矛盾的是，在39例MGUS中有3例（6%）发现N-RAS突变，这可能是有意义的 在39例MGUS肿瘤中均未发现K-RAS突变。第八， p53的失活或突变、MYC重排和失调，以及另外的 RB通路的破坏（超出细胞周期蛋白D基因的早期失调）似乎是 相对晚期进展事件与增加的增殖和不良的免疫反应相关。 预后RB通路的改变表现为p18 INK 4c的纯合缺失 （10-30%的增殖性肿瘤和细胞系）与p18表达增加（60%）相比， 细胞系和增殖性肿瘤）;这种增加可能是由于E2 F 增强基因的转录，增加增殖，但也p18。的 RB通路对p18抑制作用的不敏感性仍然无法解释， 对于一小部分已经灭活RB 1的肿瘤来说。

We continue to improve our understanding of the pathogenesis of MGUS and multiple myeloma, as summarized below. First, in a recent study not yet published we have determined that 27 of 30 multiple myeloma tumors were preceded by an MGUS tumor, providing some of the first evidence that de novo multiple myeloma is infrequent. Significantly, in four (13%) of these patients, the multiple myeloma and preceding MGUS tumors were light chain only or non-secretory. Second, we have identified seven primary translocation partners that are present in 40% of multiple myeloma tumors and comprise three translocation groups: CYCLIN D, MAF, and MMSET/FGFR3. Third, we determined that the dysregulation of a CYCLIN D gene is an early and unifying event in MGUS and multiple myeloma. Fourth, these two early oncogenic events enabled us to propose the TC (translocation/cyclin D) classification, which appears to be applicable to all MGUS and multiple myeloma tumors, but also has been demonstrated to have significance for therapeutic decisions. Fifth, we have determined that secondary translocations, which are involved in tumor progression, have structural features and chromosomal partners that distinguish them from primary translocations. Sixth, we have determined that NFKB activation either by extrinsic ligands or by mutations in at least nine components of the NFKB pathways is important for the survival and growth of normal plasma cells as well as most MGUS and MM tumors. This suggests that MGUS and MM tumors may be addicted to this pathway, and thus sensitive to drugs that inhibit the NFKB pathway. Seventh, we have determined that N-RAS mutations are much more prevalent in tumors that express CYCLIN D1 (22%) than in tumors that express CYCLIN D2 (4%), whereas K-RAS mutations have the same prevalence (17%) in both kinds of tumors. Although we presently do not understand this RAS paradox, it may be significant that N-RAS mutations were identified in 3 of 39 (6%) MGUS tumors, but K-RAS mutations were identified in none of the 39 MGUS tumors. Eighth, inactivation or mutation of p53, MYC rearrangements and dysregulation, and additional disruption (beyond the early dysregulation of a CYCLIN D gene) of the RB pathway appear to be relatively late progression events that are associated with increased proliferation and a poor prognosis. The RB pathway alterations are manifested by homozygous deletion of p18INK4c (10-30% of proliferative tumors and cell lines) vs an increase in the expression of p18 (60% of cell lines and proliferative tumors); this increase probably results from the fact that E2F enhances transcription of genes that increase proliferation, but also of p18. The insensitivity of the RB pathway to the inhibitory effects of p18 remains unexplained except for a small fraction of tumors that have inactivated RB1.