{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRAME (PReferentially expressed Antigen in MElanoma) functions as a potent modulator of transcription in cancer cells. It acts as a dominant repressor of retinoic acid receptor (RAR) signaling by binding to RAR in the presence of retinoic acid and recruiting repressive complexes, such as polycomb proteins, thereby antagonizing ligand‐induced gene activation and blocking differentiation, growth arrest, and apoptosis. In addition, PRAME has been shown to serve as a substrate recognition subunit within a Cullin2‐based E3 ubiquitin ligase complex that targets transcriptionally active promoters and interacts with components of the evolutionarily conserved EKC/KEOPS complex, underscoring its role in fine‐tuning gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its molecular repressor function, PRAME modulates cellular proliferation and differentiation in diverse malignancies. Overexpression of PRAME in cancer cells—including leukemias, breast cancer, and other solid tumors—confers a growth or survival advantage by preventing retinoic acid–induced differentiation; conversely, knockdown of PRAME restores differentiation and induces cell cycle arrest and apoptosis. These functional studies illustrate that PRAME’s aberrant expression disrupts normal cellular homeostasis and promotes oncogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its intrinsic role in tumor cell biology, PRAME is a highly immunogenic tumor‐associated antigen that is exploited for both diagnostic and therapeutic purposes. It is frequently overexpressed—often as a consequence of promoter hypomethylation and other epigenetic alterations—in a wide range of cancers and serves as a valuable marker for minimal residual disease monitoring. PRAME-specific epitopes are naturally recognized by cytotoxic T lymphocytes, and strategies to generate high-avidity PRAME-directed T cells have shown promise in preclinical models. Immunohistochemical analyses have further demonstrated that diffuse PRAME expression can aid in distinguishing malignant melanomas and metastases from benign melanocytic lesions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings establish that PRAME is not only a central regulator of transcriptional programs—by inhibiting retinoic acid signaling and modulating protein ubiquitylation—but also an attractive immunotherapeutic target and prognostic biomarker. Its dysregulated expression, mediated in part by epigenetic mechanisms, correlates with metastatic risk and adverse clinical outcomes in malignancies such as uveal and mucosal melanomas, while also playing a significant role in leukemia biology. Thus, modulation of PRAME and its downstream pathways holds promising potential for the development of targeted cancer therapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mirjam T Epping, Liming Wang, Michael J Edel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2005.07.003"}], "href": "https://doi.org/10.1016/j.cell.2005.07.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16179254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16179254"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lars Bullinger, Richard F Schlenk, Marlies Götz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRAME-induced inhibition of retinoic acid receptor signaling-mediated differentiation--a possible target for ATRA response in AML without t(15;17)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-11-2524"}], "href": "https://doi.org/10.1158/1078-0432.CCR-11-2524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23444226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23444226"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Adalberto Costessi, Nawel Mahrour, Esther Tijchon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The tumour antigen PRAME is a subunit of a Cul2 ubiquitin ligase and associates with active NFY promoters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.262"}], "href": "https://doi.org/10.1038/emboj.2011.262"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21822215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21822215"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Adalberto Costessi, Nawel Mahrour, Vikram Sharma, et al. 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