{"title":"IL-9在皮肤t细胞淋巴瘤中通过激活HIF-1α-Cofilin-1轴促进恶性t细胞的迁移传播。","authors":"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","doi":"10.1158/1541-7786.MCR-24-1020","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p><p><strong>Implications: </strong>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.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"807-821"},"PeriodicalIF":4.7000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"IL-9 Promotes Migratory Dissemination of Malignant T Cells by Activating the HIF-1α-Cofilin-1 Axis in Cutaneous T-cell Lymphoma.\",\"authors\":\"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\",\"doi\":\"10.1158/1541-7786.MCR-24-1020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p><p><strong>Implications: </strong>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.</p>\",\"PeriodicalId\":19095,\"journal\":{\"name\":\"Molecular Cancer Research\",\"volume\":\" \",\"pages\":\"807-821\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1541-7786.MCR-24-1020\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-24-1020","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
IL-9 Promotes Migratory Dissemination of Malignant T Cells by Activating the HIF-1α-Cofilin-1 Axis in Cutaneous T-cell Lymphoma.
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.
Implications: 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.
期刊介绍:
Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.