Department of Haematology/Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ, USA.
Leukemia. 2011 Jun;25(6):1026-35. doi: 10.1038/leu.2011.53. Epub 2011 Apr 5.
Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are unknown. We analyzed gene expression data sets generated on the Affymetrix U133 platform from 22 MGUS and 101 MM patients using gene-set enrichment analysis. Genes overexpressed in MM were enriched for cell cycle, proliferation and MYC activation gene sets. Upon dissecting the relationship between MYC and cell-cycle gene sets, we identified and validated an MYC activation signature dissociated from proliferation. Applying this signature, MYC is activated in 67% of myeloma, but not in MGUS. This was further confirmed by immunohistochemistry (IHC) using membrane CD138 and nuclear MYC double staining. We also showed that almost all tumors with RAS mutations expressed the MYC activation signature, and multiple mechanisms may be involved in activating MYC. MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative. Bortezomib treatment is able to overcome the survival disadvantage in patients with MYC activation.
介导从意义未明的单克隆丙种球蛋白血症（MGUS）向多发性骨髓瘤（MM）转化的事件尚不清楚。我们使用基因集富集分析方法，对 22 例 MGUS 和 101 例 MM 患者的 Affymetrix U133 平台生成的基因表达数据集进行了分析。在 MM 中过度表达的基因富集了细胞周期、增殖和 MYC 激活基因集。在剖析 MYC 和细胞周期基因集之间的关系时，我们确定并验证了一个与增殖分离的 MYC 激活特征。应用该特征，MYC 在 67%的骨髓瘤中被激活，但在 MGUS 中没有被激活。这通过使用膜 CD138 和核 MYC 双重染色的免疫组织化学（IHC）进一步得到证实。我们还表明，几乎所有具有 RAS 突变的肿瘤都表达 MYC 激活特征，并且可能涉及多种机制来激活 MYC。MYC 激活，无论是通过基因表达特征还是 IHC 评估，都与超二倍体 MM 和更短的生存时间相关，即使在非增殖性肿瘤中也是如此。硼替佐米治疗能够克服 MYC 激活患者的生存劣势。
