Table_1_Dynamic Changes in Gene Mutational Landscape With Preservation of Core Mutations in Mantle Cell Lymphoma Cells.pdf

While studies have identified a number of mutations in mantle cell lymphoma (MCL), the list may still be incomplete and contribution to the pathogenesis remains unclear. We analyzed the mutational landscape of four mantle cell lymphoma biopsies obtained during an 8-year period from the same patient with his normal cells serving as control; we also established a cell line from the final stage of the disease. Numerous mutations with high allelic burden have been identified in all four biopsies. While a large subset of mutations was seen only in individual biopsies, the core of 21 mutations persisted throughout the disease. This mutational core is also maintained in the cell line that also displays DNA-methylation and cytokine secretion profiles of the primary mantle cell lymphoma cells. This cell line is uniquely sensitive to clinically relevant inhibitors of Bruton's Tyrosine Kinase. The response to Bruton Tyrosine Kinase's inhibition is enhanced by inhibitors of CDK4/6 and mTOR. Among the mutations seen in the primary and cultured MCL cells, mutations of three genes are involved in the control of H3K4 methylation: demethylase KDM5C, present already in the early disease, and methyltransferase KMT2D and cofactor BCOR, both of which are seen late in the disease and are novel and predicted to be pathogenic. The presence of these mutations was associated with hypermethylation of H3K4. Restoration of KDM5C expression affected expression of numerous genes involved in cell proliferation, adherence/movement, and invasiveness.

尽管已有研究在套细胞淋巴瘤（mantle cell lymphoma, MCL）中鉴定出多种突变，但相关突变谱仍可能不完整，且这些突变在疾病发病机制中的作用仍未明确。本研究对同一名患者在8年间获取的4份套细胞淋巴瘤活检组织样本进行了突变谱分析，并以患者自身正常细胞作为对照；此外，我们还从该患者疾病终末期样本中建立了一株细胞系。4份活检组织样本中均鉴定出大量等位基因负荷较高的突变。尽管大部分突变仅在单份活检样本中检出，但21个突变构成的核心突变组贯穿整个疾病进程始终存在。该核心突变组在该细胞系中同样得以保留，且该细胞系的DNA甲基化谱与细胞因子分泌谱均与原代套细胞淋巴瘤细胞一致。该细胞系对临床相关的布鲁顿酪氨酸激酶（Bruton's Tyrosine Kinase）抑制剂具有独特的敏感性。CDK4/6与mTOR抑制剂可增强该细胞系对布鲁顿酪氨酸激酶抑制剂的应答反应。在原代及培养的MCL细胞检出的突变中，有3个基因的突变参与调控H3K4甲基化：早期疾病阶段即已检出的去甲基化酶KDM5C，以及疾病晚期才出现的甲基转移酶KMT2D与其辅因子BCOR，后两者均为新发现的突变且被预测具有致病性。这些突变的存在与H3K4高甲基化显著相关。恢复KDM5C的表达可影响大量与细胞增殖、黏附/迁移及侵袭性相关的基因的表达。