Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions.
Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions.
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DOI：
10.1016/j.xjidi.2021.100069
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Guenova E
中科院分区：
文献类型：
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作者：
Chang YT;Ignatova D;Hoetzenecker W;Pascolo S;Fassnacht C;Guenova E
蕈样肉芽肿（MF）是一种类型的皮肤T细胞淋巴瘤。甲亚胺（CL）被推荐作为MF的一线治疗，其主要目的是通过DNA烷基化来杀死肿瘤细胞。为了研究治疗敏感性和肿瘤特异性的程度，我们研究了直接暴露于CL的皮肤T细胞淋巴瘤皮肤细胞中克隆TCR Vβ+肿瘤细胞群的不同DNA修复途径、DNA双链断裂和肿瘤细胞增殖的基因表达。健康人T细胞对CL暴露的敏感性低于两种T淋巴瘤细胞系，导致活细胞比例较高。有趣的是，在MF病变的T细胞中，我们观察到几种重要的DNA修复途径下调，甚至完全沉默参与同源重组修复的RAD 51 AP 1，FANC 1和BRCA 2。在CL的存在下，恶性MF皮肤T细胞中的双链DNA断裂以及凋亡基因CASP3的表达显著增加。这些数据指向了靶向CL对MF皮肤肿瘤T细胞的重要作用，这支持CL用作早期皮肤淋巴瘤治疗，并且可以具有协同作用，特别是在皮肤T细胞淋巴瘤的组合皮肤定向治疗的背景下有益。
Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells through DNA alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA repair pathways, DNA double-stranded breaks, and tumor cell proliferation of clonal TCR Vβ+ tumor cell populations in cutaneous T-cell lymphoma skin cells on direct exposure to CL. Healthy human T cells were less susceptible to CL exposure than two T-lymphoma cell lines, resulting in higher proportions of viable cells. Interestingly, in T cells from MF lesions, we observed a downregulation of several important DNA repair pathways, even complete silencing of RAD51AP1, FANC1, and BRCA2 involved in homologous recombination repair. In the presence of CL, the double-stranded DNA breaks in malignant MF skin T cells increased significantly as well as the expression of the apoptotic gene CASP3. These data point toward an important effect of targeting CL on MF skin tumor T cells, which support CL use as an early cutaneous lymphoma treatment and can be of synergistic use, especially beneficial in the setting of combination skin-directed therapies for cutaneous T-cell lymphoma.