TY - JOUR
T1 - Clonotypic diversity of the T-cell receptor corroborates the immature precursor origin of cutaneous T-cell lymphoma
AU - Hamrouni, Abdelbasset
AU - Fogh, Hanne
AU - Zak, Zoulika
AU - Dum, Niels
AU - Gniadecki, Robert
PY - 2019
Y1 - 2019
N2 - Purpose: 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. Experimental Design: 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. Results: We found a substantial clonal heterogeneity in the mycosis fungoides samples with regards to TCR, and we demonstrated that lymphoma cells harboring identical TCRg sequences may harbor different TCRa and b sequences. Lack of absolute TCRa, -b, -g 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 TCRg 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 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.
AB - Purpose: 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. Experimental Design: 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. Results: We found a substantial clonal heterogeneity in the mycosis fungoides samples with regards to TCR, and we demonstrated that lymphoma cells harboring identical TCRg sequences may harbor different TCRa and b sequences. Lack of absolute TCRa, -b, -g 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 TCRg 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 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.
U2 - 10.1158/1078-0432.ccr-18-4099
DO - 10.1158/1078-0432.ccr-18-4099
M3 - Journal article
C2 - 30808775
AN - SCOPUS:85065766358
SN - 1078-0432
VL - 25
SP - 3104
EP - 3114
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -