Overexpression of hypoxia-inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides - Cutaneous T-cell lymphoma: Clinical implications

Abstract

Mycosis fungoides (MF) is the most common variant of primary cutaneous T-cell lymphoma, and decreased forkhead box P3 (FoxP3) expression has been reported in MF late stages. Hypoxia-inducible factor 1 alpha (HIF-1α) may regulate FoxP3 expression; however, it is unknown whether HIF-1α is expressed in the CD4+ T cells of MF patients and how it could affect the expression of FoxP3. Therefore, we evaluated the expression of HIF-1α and FoxP3 in CD4+ T cells obtained from the skin lesions of MF patients. We found increased cell proliferation and an increase in CD4 + T cells with an aberrant phenotype among early stage MF patients. HIF-1α was overexpressed in these CD4+ T cells. In addition, we found a decrease in the percentage of FoxP3+ cells both in the skin of MF patients, when compared with control skin samples, and with disease progression. In addition, a negative correlation was established between HIF-1α and FoxP3 expression. Skin HIF-1α expression in MF patients correlated with the extent of the affected area and increased with the disease progression. Finally, we showed that ex vivo inhibition of HIF-1α degradation increases the percentage of FoxP3+ T cells in skin lesions. Our results suggest that overexpression of HIF-1α affects the levels of FoxP3 in MF patients, which could have relevant implications in terms of disease outcome. What's new? The most common variant of cutaneous T-cell lymphoma is mycosis fungoides (MF). In MF, expression of the FoxP3 transcription factor decreases. This paper looked at the relationship between FoxP3 and another transcription factor, HIF-1 α, and their influence on MF. In skin lesions from patients with the disease, the authors found excess HIF-1 α compared with controls. They also observed that HIF-1 α levels rise, and FoxP3 levels fall, as the disease progresses. When they blocked HIF-1 α, more FoxP3+ cells arose, suggesting that overexpression of HIF-1 α does reduce FoxP3 levels and perhaps promote disease progression. © 2013 UICC.