Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.
Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.
复制标题
DOI：
10.4049/jimmunol.1202493
复制
发表时间：
2013-03-15
期刊：
影响因子：
--
通讯作者：
Singhal SB
中科院分区：
文献类型：
--
作者：
Heuck CJ;Mehta J;Bhagat T;Gundabolu K;Yu Y;Khan S;Chrysofakis G;Schinke C;Tariman J;Vickrey E;Pulliam N;Nischal S;Zhou L;Bhattacharyya S;Meagher R;Hu C;Maqbool S;Suzuki M;Parekh S;Reu F;Steidl U;Greally J;Verma A;Singhal SB
表观遗传变化在肿瘤发生过程中发挥重要作用，并通过改变基因组稳定性和调节基因表达影响肿瘤转化的初始步骤。为了表征正常浆细胞向骨髓瘤转化过程中的表观基因组变化，我们修改了HELP测定方法，使其适用于少量纯化的原代骨髓浆细胞。纳米help检测用于分析56名受试者的CD138+细胞的甲基化，这些受试者分别代表了恶性肿瘤前（MGUS）、早期和晚期骨髓瘤以及健康对照。恶性肿瘤前期和早期骨髓瘤的浆细胞具有显著的、广泛的低甲基化特征。基因特异性高甲基化发生在晚期，复发病例的代表细胞系被发现对地西他滨敏感。MGUS的异常去甲基化主要发生在CpG岛，而骨髓瘤病例中的差异甲基化位点主要发生在CpG岛之外，并影响不同的基因通路，显示了恶性前期和恶性阶段之间的质性表观遗传差异。对甲基化机制的检查显示，甲基转移酶DNMT3A在骨髓瘤中异常高甲基化和低表达，但未发生突变。在大量患者中，DNMT3A低表达也与不良的总生存期有关，这为骨髓瘤低甲基化的发生提供了新的见解。这些结果表明，在骨髓瘤形成过程中，广泛的、阶段特异性的表观遗传变化，并表明早期去甲基化可能是骨髓瘤基因组不稳定的潜在因素。我们还发现DNMT3A表达是一种新的预后生物标志物，并建议复发病例可以通过低甲基化药物进行治疗。
Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HELP assay to work with small numbers of purified primary marrow plasma cells. The nano-HELP assay was used to analyze the methylome of CD138+ cells from 56 subjects representing premalignant (MGUS), early and advanced stages of myeloma as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene specific hypermethylation was seen to occur in the advanced stages and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in MGUS occurred primarily in CpG islands while differentially methylated loci in cases of myeloma occured predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.