Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the TCyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the TCM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8+ reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergoes 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.

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ImportanceThere are limited prognostic statistics and data available on survival outcomes for patients with mycosis fungoides (MF) in Asia.ObjectiveTo determine the prognostic factors and survival outcomes of patients with MF among a cohort in China.Design, Setting, and ParticipantsThis was a retrospective cohort study of patients with MF who received treatment at a tertiary referral center for skin lymphoma (Peking University First Hospital, Beijing, China) from August 1, 2009, to August 31, 2021. Data were analyzed from September 1, 2021, to December 31, 2022.Main Outcomes and MeasuresOverall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS); for prognostic factors, hazard ratios (HRs), and adjusted HRs (aHRs; adjusted for sex, age, and overall TNMB [tumor, node, metastasis, blood] stage) determined using the Cox proportional hazards model.ResultsThe study cohort comprised 461 patients with MF (median [range] age at diagnosis, 46 [5-87] years; 275 [59.7%] men and 186 [40.3%] women; 461 [100%] Chinese). The overall 5-year rate was 82.2% for OS, 83.5% for DSS, and 79.6% for PFS. Stage-specific 5-year OS rates were 95.7% for stage IA, 93.2% for IB, 95.7% for IIA, 70.1% for IIB, 55.3% for III, and 23.6% for IV. Compared with a UK cohort, our Chinese cohort had a younger median age at diagnosis (46 years vs 54 years) and a more favorable 5-year OS (82.2% vs 75.0%); however, after adjusting for age, the discrepancy in the 5-year OS rate was diminished (77.3% vs 76.4%). Cox models revealed that unfavorable predictors of OS, PFS, and DSS, respectively, were: age older than 60 years (aHR [95% CI], 2.25 [1.28-3.96]; 2.09 [1.16-3.76]; 2.27 [1.39-3.72]); advanced TNMB stage; advanced overall stage; large-cell transformation (aHR [95% CI], 2.16 [1.17-3.99]; 2.29 [1.21-4.33]; 2.21 [1.26-3.86]); and elevated lactate dehydrogenase levels (aHR [95% CI], 3.92 [1.64-9.36]; 4.77 [1.86-12.22]; 5.05 [2.23-11.42]). Biological sex and plaque lesion type were not associated with prognosis among this study cohort.Conclusion and RelevanceThe findings of this retrospective cohort study of patients with MF in China suggest that Asian patients are diagnosed at a younger age and have a higher 5-year OS compared with patients of other races in studies in other countries (predominantly White). Prognostic factors were similar to those of previous studies, except for patient sex and plaque lesion type.

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