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posted on 2025-09-04, 07:20 authored by Ditipriya Mukherjee, Soumitra Marathe, Diksha Attrish, Vinanti Sawant, Bhavuk Dhamija, Sushant Kumar, Siddhi Wad, Moumita Basu, Neha Sharma, Hasmukh Jain, Steven R. Barthel, Rahul Purwar <p>Quadruple Immunofluorescence staining of healthy unactivated T-cells showing IL-9R, IL-2RG, CD3 and DAPI levels and STRING network analysis showing HIF-1α pathway associated proteins enriched by CoCl2 treatment in Jurkat cells.</p>
Funding
Indian Council of Medical Research (ICMR)
Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Ministry of Science and Technology, India (RGCB)
History
ARTICLE ABSTRACT
Cutaneous T-cell lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. In this study, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T cells. Stimulation of IL-9R–expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the promigratory and oxygen-sensing transcription factor hypoxia-inducible factor (HIF)-1α. High-throughput quantitative proteomic analyses of pseudohypoxic malignant T cells identified the actin-modulating protein cofilin-1 (CFL-1) as a promigratory CTCL-intrinsic target downstream of IL-9–HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked coexpression of CFL-1 with HIF-1α in both IL-9–treated human lymphoma cell lines and in patient CTCL skin biopsies compared with normal controls. Genetic knockdown of IL9R or HIF1A in human T-cell lymphoma lines by RNAi significantly reduced both HIF-1α and CFL-1 coexpression and reversed IL-9–induced migration. Finally, pharmacologic antagonism of HIF-1α activity using the FDA-designated orphan drug echinomycin significantly abrogated IL-9–triggered migration of both malignant T-cell lines and patient-derived T-cell lymphoma cells from CTCL biospecimens.
Our results uncover a CTCL-intrinsic IL-9–HIF-1α–CFL-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and CFL-1 as promising therapeutic targets to mitigate IL-9–induced CTCL dissemination.
