Global methylation patterns in Primary Plasma Cell leukemia

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), which is associated with a very poor prognosis. Specific molecular patterns distinguish pPCL in comparison to MM and in relation to main genomic alterations. In the present study, a whole-genome methylation profiling analysis by high-density array revealed a global gene hypomethylation profile in pPCL. Lower methylation levels were particularly observed in the promoter and 5’ untranslated regions (5’UTR), whereas higher levels were evidenced in gene body or 3’ untranslated regions (3’UTR). CpG islands (CGI) resulted largely hypomethylated, whereas higher methylation levels were observed in CGI distal regions. Peculiar differential methylation patterns were identified in association to major chromosomal aberrations and DIS3 mutational status and involved genes playing roles in cell migration, bone metabolism, transcription regulation or DNA damage response. Finally, decreasing methylation levels were evidenced for few genes in association to MM disease progression, from healthy condition to MM and pPCL. Our data may provide new insights into the molecular characterization of pPCL patients, thus being potentially useful in the prognostic stratification or identification of novel molecular targets. Bisulphite converted DNA from the 14 samples were hybridised to the Illumina Infinium HumanMethylation450 BeadChip array (Illumina Inc., San Diego, CA, USA)原发性浆细胞白血病（primary plasma cell leukemia, pPCL）是多发性骨髓瘤（multiple myeloma, MM）的一种罕见且侵袭性较强的亚型，预后极差。与MM相比，pPCL具有独特的分子特征谱，并伴随特异性的主要基因组改变。本研究通过高密度芯片阵列开展全基因组甲基化谱分析，发现pPCL呈现全基因组基因低甲基化特征：启动子区域与5'非翻译区（5’UTR）的甲基化水平尤为偏低，而基因本体区域或3'非翻译区（3’UTR）的甲基化水平则相对更高。CpG岛（CGI）整体呈低甲基化状态，而其远端区域的甲基化水平更高。本研究还鉴定出与主要染色体畸变及DIS3突变状态相关的特异性差异甲基化模式，这些模式涉及参与细胞迁移、骨代谢、转录调控及DNA损伤应答的功能基因。最后，在从健康状态到MM再到pPCL的多发性骨髓瘤疾病进展过程中，少量基因的甲基化水平呈逐渐降低趋势。本研究数据可为pPCL患者的分子特征解析提供新的见解，有望用于pPCL的预后分层及新型分子靶点的发掘。本研究将14例样本的亚硫酸氢盐转化DNA与Illumina Infinium人类甲基化450微珠芯片阵列（美国加利福尼亚州圣地亚哥Illumina公司）进行杂交实验。