High Expression of IKZF2 in Malignant T Cells Promotes Disease Progression in Cutaneous T Cell Lymphoma

Abstract

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, CTCL may manifest as aggressive clinical behavior and lead to a poor prognosis. The mechanism of disease progression in CTCL remains unknown. Here, with a large clinical cohort, we identified that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage-dependent overexpression in the malignant T cells in MF lesions. IKZF2 is specifically over-expressed in advanced-stage MF lesions, correlates with poor patient prognosis. Mechanistically, IKZF2 overexpression promotes CTCL progression via inhibiting malignant cell apoptosis and may contribute to tumor immune escape by downregulating MHC-II molecules and up-regulating the production of anti-inflammatory cytokine IL-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk CTCL and pave the way for future targeted therapy.

Differential molecular programs of cutaneous anaplastic large cell lymphoma and CD30-positive transformed mycosis fungoides

“…We detected GATA3, previously reported as a diagnostic candidate to differentiate cALCL from CD30+ TMF ( 15 ), exhibited distinct expression in CD30+ TMF in our data ( Figure 2C ). IKZF2, with its reported role in LCT ( 48 ), showed higher expression in CD30+ TMF when compared ( Figure 2C ).…”

“…The precise mechanism remains unknown, but it is hypothesized that the interaction between HLA type II-expressing lymphoma cells and CD4+ T cells may contribute to tumor immunity in cALCL, potentially contributing to spontaneous tumor regression and improved outcomes. In contrast, IKZF2 transactivation was enriched in CD30+ TMF, and IKZF2 has been reported to downregulate HLA type II genes in MF cells, which may help to CD30+ TMF cells escape the anti-tumor immunity ( 48 ). Further research is warranted to explore the expression and function of HLA type II genes in both diseases.…”