Abstract
Progressive DNA damage and worsening aneuploidy are associated with the development of highly aggressive CTCL. We immunostained MF skin lesions for the phosphorylated DNA double-strand break repair genes γH2AX and 53BP1 and phosphorylated/activated ATM (pATM) and found that ongoing double-strand DNA breaks were frequent within the malignant T cells even in clinically stable MF skin lesions. IL-6, a product of senescent cells, is the second most highly expressed cytokine in MF. Immunostaining demonstrated the senescence marker p21Cip1 was increased in a stage specific manner in MF and localized to OX40L+CD40L+ dendritic cells. These DC also expressed thioredoxin (TXN), indicating production of reactive oxygen species (ROS) and were found clustered closely together with malignant and benign T cells. ROS production by senescent cells is known to drive ROS-induced DNA damage in neighboring cells. We therefore immunostained T cells near senescent DC for evidence of oxidative stress (TXN) and double-strand DNA breaks (γH2AX). We found a stage specific increase in T cells experiencing oxidative stress and ongoing DNA damage in T cells neighboring senescent DC. Malignant T cells were primarily affected but some CD7+ benign infiltrating T cells showed evidence of DNA damage in later stage MF (IIA, IIB). Our results suggest that ROS produced by senescent DC induces DNA damage in T cells and may drive T cell transformation and tumor progression. These studies suggest a possible role for senolytic therapies in the treatment of CTCL.
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