PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma

• Published in: Blood 2022-01, Vol.139 (4), p.554-571
• Main Authors: Liu, Fengjie, Gao, Yumei, Xu, Bufang, Xiong, Shan, Yi, Shengguo, Sun, Jingru, Chen, Zhuojing, Liu, Xiangjun, Li, Yingyi, Lin, Yuchieh, Wen, Yujie, Qin, Yao, Yang, Shuxia, Li, Hang, Tejasvi, Trilokraj, Tsoi, Lam, Tu, Ping, Ren, Xianwen, Wang, Yang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; DNA-Binding Proteins - genetics; Female; Gene Amplification; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Humans; Lymphoid Neoplasia; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Mycosis Fungoides - genetics; Mycosis Fungoides - pathology; RNA-Binding Proteins - genetics; Skin Neoplasms - genetics; Skin Neoplasms - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021012091

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-κB 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. •Chr7q21.3 amplification drives ectopic PEG10 expression and potentiates large-cell transformation in CTCL via a PEG10/KLF2/ NF-κB axis.•Pharmacological targeting PEG10 reverses the phenotypes of large-cell transformation in CTCL. [Display omitted]