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人体内源逆转录病毒作为TP53-突变扩散大B细胞淋巴瘤的表观遗传治疗点

Ying Fang¹, Mu-Chen Zhang¹, Yang He¹

¹Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Signal transduction and targeted therapy

|October 5, 2023

概括

在扩散性大B细胞淋巴瘤 (DLBCL) 中TP53突变会导致治疗耐药性. 针对SUV39H1和内源逆转录病毒的Decitabine加R-CHOP疗法通过重编程瘤微环境来改善TP53突变DLBCL的结果.

科学领域:

血液学血液学血液学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

TP53突变 (TP53mut) 在10-20%的扩散性大B细胞淋巴瘤 (DLBCL) 病例中被发现.
TP53mut赋予了对标准DLBCL疗法的耐药性,包括免疫化疗,高剂量化疗,干细胞移植和CAR T细胞疗法.
针对DLBCL中的TP53mut仍然是一个重大的临床挑战.

研究的目的:

评估TP53mut对DLBCL预后和治疗反应的影响.
为了研究decitabine与R-CHOP结合用于TP53mut DLBCL的治疗潜力.
阐明TP53突变驱动DLBCL背后的分子机制及其对德西的反应.

主要方法:

在667名新诊断的DLBCL患者中分析TP53mut状态,这些患者接受了R-CHOP或decitabine加R-CHOP (DR-CHOP) 治疗.
基因组丰富分析以确定TP53mut DLBCL中失调的途径.
评估SUV39H1表达,H3K9三甲基化 (H3K9me3) 和内源逆转录病毒 (ERV) 的表达.
使用DLBCL细胞系的体外研究和使用患者衍生的异种移植模型的体内研究.

主要成果:

在R-CHOP治疗的DLBCL中,TP53mut独立预测了较差的预后,但这被DR-CHOP治疗减轻了.
TP53mut DLBCL显示病毒调节途径被抑制,免疫调节受损,SUV39H1和H3K9me3增加,导致ERV沉默和免疫抑制瘤微环境.
德西塔降低了SUV39H1的调节,降低了ERV上的H3K9me3,并诱导了ERV的表达,激活干扰素程序和T细胞反应.
在TP53mut DLBCL模型和通过SUV39H1-H3K9me3-ERVs轴的患者中,联合德西他宾和多克索鲁比辛治疗改善了抗瘤作用.

结论:

TP53mut DLBCL的特点是ERV调节电路,该电路在表观遗传上重新编程瘤微环境.
通过准SUV39H1-H3K9me3-ERVs轴,DR-CHOP疗法为TP53mut DLBCL提供了一个有希望的治疗策略.
了解和准ERV法规为治疗TP53突变驱动的癌症提供了一种新的方法.

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