Clonotypic diversity of the T-cell receptor corroborates the immature precursor origin of cutaneous T-cell lymphoma

Purpose: Mycosis fungoides (MF) is one of the most common types of extranodal T-cell lymphomas, considered to be caused by malignant transformation of the mature T-cell residing in the skin. However, some clinical observations such as the multifocal distribution of MF lesions or patterns of relapse after radiotherapy are not readily explainable by the mature T-cell origin theory. Experimental Design: We have performed a detailed analysis of T-cell receptor (TCR) rearrangements in single malignant cells and in biopsies from MF tumors composed of >80% of malignant cells using next-generation sequencing (NGS) to pinpoint the relationship between neoplastic cells in MF. We have also aimed to detect malignant, circulating T-cell by whole blood TCR sequencing. Results: We found a substantial clonal heterogeneity in the MF samples with regards to TCR, and we demonstrated that lymphoma cells harboring identical TCR sequences may harbor different TCRα and β sequences. Lack of absolute TCRα, -β, - monoclonality was further confirmed by TCR amplification and sequencing from microdissected lymphoma cells. We have also found the TCR rearrangements characteristic for lymphoma cells in patients' peripheral blood despite lack of leukemic blood involvement, however the circulating TCR clonotype did not always represent the dominant cutaneous clonotype. Conclusions: These findings can be explained by a model where malignant transformation takes place during early T-cell development giving rise to circulating pre-malignant clones which home to the skin producing clinically apparent lesions of cutaneous lymphoma. Therapeutic strategies in T-cell lymphoma should therefore target those early lymphoma precursor cells.

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