Differential Response of Mycosis Fungoides Cells to Vorinostat

Abstract

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.

Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides

“…The exact mechanism behind these differences is not currently understood but is likely due to the fact that the cell lines originate from different patients and exhibit molecular heterogeneity that may alter their response to therapeutics. These findings are in line with previous studies demonstrating that medications like vorinostat differentially modulate the expression of chemokine receptors and ligands in HH and MyLa cell lines 90 , and with the clinical observation that many therapeutics may only produce desired clinical outcomes in small percentages of MF patients 91 , 92 .…”

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat

“…Given that vorinostat was the first HDACi to receive FDA approval for the treatment of CTCL, it is imperative to develop a thorough understanding of the precise molecular mechanism by which this drug exerts its action against this lymphoma pathology. Therefore, a recent study was undertaken to evaluate its effect on cells involved in a common form of CTCL, mycosis fungoides (MF), characterized by the accumulation of malignant CD4 + T lymphocytes in the skin [ 103 ]. In response to vorinostat treatment, a reduction in the expression of certain proteins in MF cells was recorded in both HH and Myla cell lines.…”