PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma
PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma
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7q21.3 处的 PEG10 扩增增强皮肤 T 细胞淋巴瘤的大细胞转化
DOI：
10.1182/blood.2021012091
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发表时间：
2022-01-27
期刊：
影响因子：
20.3
通讯作者：
Wang, Yang
中科院分区：
文献类型：
--
作者：
Liu, Fengjie;Gao, Yumei;Wang, Yang
蕈样真菌病（Mycosis fungoides， MF）是最常见的皮肤t细胞淋巴瘤，晚期发生大细胞转化（LCT），表现为侵袭性行为，对治疗有耐药性，预后差，但其机制尚不清楚。为了确定LCT的分子驱动因素，我们收集了133名MF患者的肿瘤样本，对49名晚期MF患者进行了全转录组测序，然后进行了综合拷贝数推断和基因组杂交。LCT肿瘤表现出独特的转录程序和丰富的chr7q基因表达。父系表达基因10 （PEG10）是一个7q21.3的印迹基因，在7q21.3扩增的驱动下，在LCT的恶性T细胞中异位表达。机制上，在体外和体内模型中，异常的PEG10表达增加了细胞大小，促进了细胞增殖，并通过PEG10/KLF2/NF-kappa B轴赋予了治疗抗性。药物靶向PEG10逆转了LCT的增殖和治疗耐药表型。我们的研究结果揭示了LCT的新分子机制，并表明PEG10抑制可能是晚期侵袭性t细胞淋巴瘤的一种有希望的治疗方法。
Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-kappa B axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.