PRAME

Official Full Name

PRAME nuclear receptor transcriptional regulator

Organism

Homo sapiens

GeneID

23532

Background

This gene encodes an antigen that is preferentially expressed in human melanomas and that is recognized by cytolytic T lymphocytes. It is not expressed in normal tissues, except testis. The encoded protein acts as a repressor of retinoic acid receptor, and likely confers a growth advantage to cancer cells via this function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

Synonyms

MAPE; OIP4; CT130; OIP-4;

Protein Sequence

MERRRLWGSIQSRYISMSVWTSPRRLVELAGQSLLKDEALAIAALELLPRELFPPLFMAAFDGRHSQTLKAMVQAWPFTCLPLGVLMKGQHLHLETFKAVLDGLDVLLAQEVRPRRWKLQVLDLRKNSHQDFWTVWSGNRASLYSFPEPEAAQPMTKKRKVDGLSTEAEQPFIPVEVLVDLFLKEGACDELFSYLIEKVKRKKNVLRLCCKKLKIFAMPMQDIKMILKMVQLDSIEDLEVTCTWKLPTLAKFSPYLGQMINLRRLLLSHIHASSYISPEKEEQYIAQFTSQFLSLQCLQALYVDSLFFLRGRLDQLLRHVMNPLETLSITNCRLSEGDVMHLSQSPSVSQLSVLSLSGVMLTDVSPEPLQALLERASATLQDLVFDECGITDDQLLALLPSLSHCSQLTTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESYEDIHGTLHLERLAYLHARLRELLCELGRPSMVWLSANPCPHCGDRTFYDPEPILCPCFMPN

Open

Disease

Malignant haematopoietic neoplasm, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

PRAME (Preferentially Expressed Antigen in Melanoma) was initially identified in melanoma due to its ability to be recognized by cytotoxic T lymphocytes. Located at chromosome 22q11.22, the gene contains multiple exons and undergoes alternative splicing to produce several transcript variants. The PRAME protein functions as a substrate recognition component of the Cul2-RING (CRL2) E3 ubiquitin ligase complex, playing a crucial role in protein ubiquitination and degradation. Notably, PRAME is minimally expressed in normal tissues except for the testis, making it an attractive target for tumor immunotherapy. The PRAME gene family has expanded during evolution, with multiple paralogs in the human genome, suggesting roles in reproductive development. Its promoter region is enriched with transcription factor binding sites, and expression is tightly regulated epigenetically, with DNA methylation changes contributing to aberrant expression in tumors.

Figure 1. PRAME is expressed in early progenitor cells and normally silenced in melanocytes, but promoter demethylation leads to its reactivation in melanoma cells. (Blount SL, et al., 2024)

Biological Functions and Molecular Mechanisms

PRAME exerts dual intracellular functions: transcriptional regulation and protein degradation. In the nucleus, it inhibits retinoic acid receptor (RAR) signaling by directly binding RARA, RARB, and RARG, allowing cancer cells to evade differentiation and apoptosis. Mechanistically, PRAME recruits epigenetic regulators such as polycomb repressive complexes (PRCs) to target promoters, promoting repressive histone modifications like H3K27me3 and suppressing gene transcription. As a component of the CRL2 complex, PRAME mediates ubiquitination and degradation of specific proteins, including truncated forms of MSRB1/SEPX1. PRAME also interacts with nuclear transcription factor Y (NFY) at active promoters, suggesting a role in chromatin dynamics and adaptive cellular regulation.

Expression Patterns and Clinical Significance

Hematologic Malignancies

PRAME expression varies across leukemia subtypes. In acute myeloid leukemia (AML), M3 (acute promyelocytic leukemia) shows an 80% positivity rate, whereas M2 and M5 subtypes exhibit 33.3% and 28.6%, respectively. Acute lymphoblastic leukemia (ALL) shows approximately 28.6% positivity. Patients with chromosomal abnormalities exhibit higher PRAME expression, correlating with genomic instability. Due to its absence in normal hematopoietic tissue, PRAME serves as a sensitive and specific marker for minimal residual disease (MRD) monitoring.

Solid Tumors

In melanoma, PRAME is both a diagnostic marker and a therapeutic target, although its expression can occasionally appear in benign melanocytic lesions, which requires careful pathological interpretation. In triple-negative breast cancer (TNBC), PRAME expression is observed in ~38.8% of cases but absent in normal breast tissue, supporting its potential as an immunotherapy target. Across various solid tumors, including thyroid and lung cancers, PRAME expression correlates with tumor progression and poor prognosis, making it an independent prognostic indicator.

Advances in Immunotherapeutic Targeting

PRAME’s tumor-specific expression and immunogenicity have spurred multiple immunotherapy approaches. TCR-engineered T cells (TCR-T) targeting PRAME effectively eliminate leukemia and solid tumor cells in preclinical studies. PRAME-derived peptide and full-length protein vaccines induce strong antigen-specific T cell responses in clinical trials. Bispecific antibodies engaging both PRAME and T cell surface molecules (e.g., CD3) have been developed to redirect T cell cytotoxicity. Epigenetic drugs, such as DNA methyltransferase inhibitors, are being explored to modulate PRAME expression and enhance therapy efficacy. Challenges include tumor heterogeneity, immunosuppressive microenvironments, and potential off-target effects, particularly in testis tissue. Next-generation strategies aim to enhance T cell persistence, combine checkpoint inhibitors, and implement conditional activation systems.

Future Perspectives and Challenges

Despite being an ideal tumor immunotherapy target, PRAME research faces challenges in elucidating tissue-specific regulation, understanding its role in tumor immune editing, and standardizing detection methods. Strategies to overcome antigen escape, including combination therapies targeting multiple tumor antigens, are under development. Additionally, assessing PRAME’s physiological function in testis tissue is critical to ensure therapeutic safety. Advances in gene editing, single-cell analyses, and AI-based predictive modeling are expected to refine our understanding of PRAME’s molecular networks, driving more precise and personalized immunotherapeutic strategies.

PRAME remains a key molecule in tumor biology and immunotherapy, with its unique expression profile and multifaceted functions offering novel insights for cancer diagnosis and treatment. Ongoing research from basic mechanisms to clinical translation continues to expand the boundaries of tumor immunology and patient-specific therapy.

Reference

Cassalia F, Danese A, Tudurachi I, et al. PRAME Updated: Diagnostic, Prognostic, and Therapeutic Role in Skin Cancer. Int J Mol Sci. 2024 Jan 27;25(3):1582.
Lezcano C, Jungbluth AA, Busam KJ. PRAME Immunohistochemistry as an Ancillary Test for the Assessment of Melanocytic Lesions. Surg Pathol Clin. 2021 Jun;14(2):165-175.
Blount SL, Liu X, McBride JD. The Utilization of PRAME in the Diagnosis, Prognosis, and Treatment of Melanoma. Cells. 2024 Oct 20;13(20):1740.

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