{
  "abstract": "Introduction: Venetoclax has transformed the treatment of chronic lymphocytic leukemia (CLL), yet therapeutic resistance remains a major clinical challenge. In addition to leukemia cell-intrinsic mechanisms, interactions with the immune microenvironment can profoundly reduce venetoclax sensitivity. We previously identified sphingosine kinase 2 (SPHK2) as a therapeutic vulnerability underlying T-cell-supported venetoclax resistance. Here, we investigated the contribution of CD4 ⁺ and CD8 ⁺ T cell subsets and their extracellular vesicles (EVs) to this resistant phenotype and evaluated the therapeutic activity of the SPHK2 inhibitor opaganib in vivo .\n\nMethods: We evaluated the role of activated CD4 ⁺ and CD8 ⁺ T cells and their EVs in the development of the venetoclax-resistant phenotype in primary CLL cells. The in vivo activity of opaganib was assessed in a xenograft model generated by co-engraftment of primary CLL cells with autologous activated T cells. Mice were treated with venetoclax, opaganib, or their combination, and leukemic burden and the T cell compartment were evaluated. Anti-apoptotic BCL-2 family proteins were also assessed in residual leukemic cells.\n\nResults: Activated CD4 ⁺ , but not CD8 ⁺ , T cells induced leukemic cell activation and venetoclax resistance, and CD4 ⁺ T cell-derived EVs were sufficient to reproduce this phenotype. In vivo , venetoclax monotherapy failed to reduce leukemic burden, confirming that adaptive interactions with the immune microenvironment are sufficient to sustain therapeutic resistance. Although opaganib alone showed minimal antileukemic activity, its combination with venetoclax reduced splenic leukemic burden by approximately 50% and remodeled the tumor-associated T-cell compartment, without consistent modulation of anti-apoptotic BCL-2 family proteins in residual leukemic cells.\n\nDiscussion: These findings are consistent with the notion that the therapeutic effects of opaganib extend beyond leukemic-cell-intrinsic mechanisms and may include modulation of the immune microenvironment. Our study shows that opaganib reduces microenvironment-driven venetoclax resistance in a preclinical CLL model in vivo , supporting its clinical evaluation in combination with BCL-2 inhibition.",
  "abstract_shown": true,
  "affiliations": [
    "Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Academia Nacional de Medicina",
    "Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires (UBA)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)",
    "Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología",
    "The Feinstein Institutes for Medical Research",
    "Instituto Alexander Fleming (IAF)",
    "Hospital Alemán",
    "Fundaleu",
    "Centro Médico Km 41",
    "Hospital General de Agudos Dr. Teodoro Álvarez",
    "Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Cátedra I de Inmunología"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Valeria Judith Sarapura Martínez"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Paula Soledad Pérez"
    },
    {
      "affs": [
        3
      ],
      "name": "Anita Ng"
    },
    {
      "affs": [
        3
      ],
      "name": "Yu-Ju Chen"
    },
    {
      "affs": [
        3
      ],
      "name": "Kelly Wong"
    },
    {
      "affs": [
        0
      ],
      "name": "Chiara Cassarino"
    },
    {
      "affs": [
        4
      ],
      "name": "Rosario Custidiano"
    },
    {
      "affs": [
        5
      ],
      "name": "Carolina Mahuad"
    },
    {
      "affs": [
        6
      ],
      "name": "Miguel A. Pavlovsky"
    },
    {
      "affs": [
        7
      ],
      "name": "Raimundo Fernando Bezares"
    },
    {
      "affs": [
        8
      ],
      "name": "Martin Bertini"
    },
    {
      "affs": [
        0,
        9
      ],
      "name": "Mercedes Borge"
    },
    {
      "affs": [
        0,
        9
      ],
      "name": "Mónica Vermeulen"
    },
    {
      "affs": [
        0
      ],
      "name": "Pablo Elías Morande"
    },
    {
      "affs": [
        0
      ],
      "name": "Mirta Giordano"
    },
    {
      "affs": [
        1,
        9
      ],
      "name": "Matías Ostrowski"
    },
    {
      "affs": [
        3
      ],
      "name": "Nicholas Chiorazzi"
    },
    {
      "affs": [
        3
      ],
      "name": "Shih-Shih Chen"
    },
    {
      "affs": [
        0,
        9
      ],
      "name": "Romina Gamberale"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/av4vkmdehvxzp.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1968413",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717244/?tool=EBI",
  "id": "av4vkmdehvxzp",
  "issns": [
    "1664-3224"
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  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1968413/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
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      "openalex",
      "2716|Chronic Lymphocytic Leukemia Research"
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  "openalex": "W7222053372",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1968413/pdf",
  "pmcid": "PMC13717244",
  "pmid": "42959570",
  "published": "2026-10-15",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/av4vkmdehvxzp.ris",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Chronic Lymphocytic Leukemia Research",
      "subfield": "human-genetics"
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  ],
  "title": "T cell–driven venetoclax resistance in chronic lymphocytic leukemia: in vivo preclinical activity of opaganib",
  "title_text": "T cell–driven venetoclax resistance in chronic lymphocytic leukemia: in vivo preclinical activity of opaganib",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:21:36Z",
  "url": "https://research.draconitic.com/paper/av4vkmdehvxzp",
  "venue": "Frontiers in Immunology",
  "versions": []
}