Molecular Pathogenesis of Multiple Myeloma

我们继续提高对MGUS和多发性骨髓瘤发病机制的理解，总结如下。首先，在最近一项尚未发表的研究中，我们已经确定了30例多发性骨髓瘤中有27例在MGUS肿瘤之前，这提供了一些新发多发性骨髓瘤罕见的第一证据。值得注意的是，在这些患者中，4例(13%)多发性骨髓瘤和先前的MGUS肿瘤仅为轻链或非分泌性。其次，我们已经确定了七个主要易位伙伴，它们存在于40%的多发性骨髓瘤中，包括三个易位组：细胞周期蛋白D、MAF和MMSET/FGFR3。第三，我们确定细胞周期蛋白D基因的失调是MGUS和多发性骨髓瘤的早期和统一事件。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，该分类似乎适用于所有MGUS和多发性骨髓瘤，但也已被证明对治疗决策具有重要意义。第五，我们已经确定了与肿瘤进展有关的继发性易位具有区别于原发易位的结构特征和染色体配对。第六，我们已经确定，通过外源性配体或通过至少九个NFKB通路成分的突变激活NFKB对于正常浆细胞以及大多数MGUS和MM肿瘤的生存和生长是重要的。这表明MGUS和MM肿瘤可能对这一途径上瘾，因此对抑制NFKB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D1的肿瘤(22%)中比在表达细胞周期蛋白D2的肿瘤(4%)中更常见，而K-RAS突变在两种肿瘤中的发生率相同(17%)。虽然我们目前还不了解这一RAS悖论，但在39例MGUS肿瘤中有3例(6%)发现了N-RAS突变，但在39例MGUS肿瘤中没有一例发现K-RAS突变。第八，P53的失活或突变、MYC重排和调节失调，以及Rb途径的额外破坏(超出早期细胞周期蛋白D基因的调节失调)似乎是相对较晚的进展事件，与增殖增加和预后不良有关。Rb通路的改变表现为p18INK4c的纯合缺失(10-30%的增殖性肿瘤和细胞系)与p18的表达增加(60%的细胞系和增殖性肿瘤)；这种增加可能是由于E2F增强了促进增殖的基因的转录，但也增强了p18的转录。Rb通路对p18的抑制作用不敏感的原因仍不清楚，除了一小部分已失活RB1的肿瘤。

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.