Abstract
Mycosis fungoides is one of the most common types of extranodal T-cell lymphomas, considered to be caused by malignant transformation of the mature T cells residing in the skin. However, some clinical observations such as the multifocal distribution of mycosis fungoides lesions or patterns of relapse after radiotherapy are not readily explainable by the mature T-cell origin theory. We have performed a detailed analysis of T-cell receptor (TCR) rearrangements in single malignant cells and in biopsies from mycosis fungoides tumors composed of >80% of malignant cells using next-generation sequencing (NGS) to pinpoint the relationship between neoplastic cells in mycosis fungoides. We have also aimed to detect malignant, circulating T-cell by whole blood TCR sequencing. We found a substantial clonal heterogeneity in the mycosis fungoides samples with regards to TCR, and we demonstrated that lymphoma cells harboring identical TCRγ sequences may harbor different TCRα and β sequences. Lack of absolute TCRα, -β, -γ 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 the lack of leukemic blood involvement; however, the circulating TCRγ clonotype did not always represent the dominant cutaneous clonotype. These findings can be explained by a model where malignant transformation takes place during early T-cell development giving rise to circulating premalignant 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.
Highlights
Neoplasms from T cells arise often in extranodal tissue, most commonly in the skin
We found a substantial clonal heterogeneity in the mycosis fungoides samples with regards to T-cell receptor (TCR), and we demonstrated that lymphoma cells harboring identical TCRg sequences may harbor different TCRa and b sequences
These findings can be explained by a model where malignant transformation takes place during early T-cell development giving rise to circulating premalignant clones, which home to the skin producing clinically apparent lesions of cutaneous lymphoma
Summary
Neoplasms from T cells arise often in extranodal tissue, most commonly in the skin. Mycosis fungoides is the most common cutaneous T-cell lymphoma (CTCL), presenting initially as red, scaly patches comprising neoplastic T cells that may further progress into tumors and eventually disseminate [1, 2]. Advanced mycosis fungoides is a prototypical disease displaying key features of a peripheral T-cell lymphoma: chronic, relapsing course, lowgrade proliferation, chemotherapy resistance, and 5-year mortality approaching 50% [2, 3]. Mycosis fungoides displays a mature memory T-cell phenotype and is considered to be caused by malignant transformation of a mature T-cell residing in the skin. TCR is an excellent marker of T-cell lineage because TCR d-, g-, b-, and a-loci become sequentially rearranged during intrathy-
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More From: Clinical cancer research : an official journal of the American Association for Cancer Research
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