Table_6_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.

尽管研究已经鉴定出多种在浆细胞样淋巴瘤（MCL）中的突变，但该列表可能仍不完整，其对发病机制的贡献尚不明确。我们在过去8年间对同一患者的四份MCL活检样本进行了突变谱分析，以患者的正常细胞作为对照；我们还从疾病的终末期建立了细胞系。在所有四份活检样本中均发现了具有高等位基因负荷的众多突变。虽然大部分突变仅在个别活检样本中观察到，但21个突变的核心在整个疾病过程中持续存在。这一突变核心亦在细胞系中得到保留，该细胞系还表现出与原发性MCL细胞相似的DNA甲基化和细胞因子分泌谱。该细胞系对布鲁顿酪氨酸激酶（Bruton's Tyrosine Kinase）的临床相关抑制剂具有独特敏感性。CDK4/6和mTOR抑制剂的联合使用可增强对布鲁顿酪氨酸激酶抑制剂的反应。在原发和培养的MCL细胞中观察到的突变中，有三基因突变与H3K4甲基化的控制相关：存在于早期疾病的去甲基化酶KDM5C，以及存在于疾病晚期的甲基转移酶KMT2D和辅助因子BCOR，两者均为新发现，并被预测为致病性。这些突变的存在与H3K4的超甲基化相关。KDM5C表达的恢复影响了参与细胞增殖、粘附/运动和侵袭性等多个基因的表达。