Hunter Zachary R, Xu Lian, Yang Guang, Tsakmaklis Nicholas, Vos Josephine M, Liu Xia, Chen Jie, Manning Robert J, Chen Jiaji G, Brodsky Philip, Patterson Christopher J, Gustine Joshua, Dubeau Toni, Castillo Jorge J, Anderson Kenneth C, Munshi Nikhil M, Treon Steven P
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Blood. 2016 Aug 11;128(6):827-38. doi: 10.1182/blood-2016-03-708263. Epub 2016 Jun 14.
Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM.
全基因组测序已在华氏巨球蛋白血症（WM）中鉴定出高度普遍的体细胞突变，包括MYD88、CXCR4和ARID1A。这些以及其他体细胞突变对WM转录调控的影响仍有待阐明。我们对57例WM患者进行了下一代转录谱分析，并将结果与健康供体B细胞进行了比较。与健康供体相比，WM患者样本中VDJ重组基因DNTT、RAG1和RAG2的表达大幅增强，但AICDA基因未增强。无论CXCR4突变状态如何，与CXCR4信号传导相关的基因也上调，包括CXCR4、CXCL12和VCAM1，这表明CXCR4信号传导在所有WM患者中具有潜在作用。WM转录谱与健康记忆B细胞和循环B细胞同样不同，这可能是由于分化增加而非细胞来源所致。CXCR4突变的谱与B细胞分化减弱以及肿瘤抑制因子的抑制相对应，这些肿瘤抑制因子由MYD88突变上调，其方式与单独MYD88突变的情况相比，与TLR4信号传导的抑制有关。对首要发现进行的启动子甲基化研究未能解释这种抑制作用，但在MYD88野生型患者中发现了异常甲基化模式。CXCR4和MYD88转录呈负相关，表现出等位基因特异性转录偏向，并且与CXCL13一起，与骨髓疾病累及有关。还描述了具有野生型MYD88、突变型ARID1A、WM家族易感性、6号染色体q臂缺失、3号染色体q臂扩增和4号染色体三体的患者的不同基因表达谱。这些发现为WM的分子发病机制提供了新的见解，并为靶向治疗策略提供了机会。
