{
  "abstract": "Background: Core binding factor acute myeloid leukemia (CBF-AML) driven by the CBFB-MYH11 fusion oncogene is associated with high initial remission rates, yet 30%–50% of patients ultimately relapse. While immune evasion is a recognized hallmark of leukemia progression, the precise mechanisms orchestrated by the CBFB-MYH11 oncogene remain poorly understood. Furthermore, the role of transforming growth factor-beta (TGFβ) in hematological malignancies is highly controversial, often viewed as a tumor suppressor in early hematopoiesis rather than a driver of immune evasion.\n\nMethods: We used an inducible Cbfb-MYH11 knock-in mouse model and primary AML cell transplantation to profile the immune microenvironment during leukemogenesis. We integrated flow cytometry, bulk and single-cell RNA sequencing (scRNA-seq), CUT&RUN, luciferase reporter assay, ChIP-qPCR, and ChIP-Seq. Functional in vitro T-cell suppression assays and in vivo engraftment using Pdcd1 knockout (PD-1 KO) mice, and treatments with the anti-PD-L1 antibody, TGFβ receptor inhibitor galunisertib, and cytarabine were performed to evaluate immunotherapeutic vulnerabilities.\n\nResults: Leukemogenesis in the Cbfb-MYH11 model was accompanied by profound T-cell suppression and exhaustion, and the AML cells effectively inhibited T-cell proliferation in co-culture. Transcriptomic profiling identified marked upregulation of Cd274 (PD-L1) and Tgfb1 in AML cells. Mechanistically, CUT&RUN and ChIP-Seq demonstrated that the CBFβ-SMMHC fusion oncoprotein and its co-factor RUNX1 directly bind to the promoter regions of CD274 and TGFB1 to transcriptionally activate their expression in both murine and human AML models. While genetic ablation of PD-1 in host mice provided only limited survival benefits, pharmacological blockade of TGFβ effectively restored T cell function and delayed AML progression. Importantly, combining cytarabine with galunisertib provided superior disease control, reversed T cell exhaustion, and significantly prolonged survival compared with chemotherapy alone, which can be further enhanced by targeting PD-L1/PD-1.\n\nConclusions: The CBFB-MYH11 oncogene directly orchestrates an immunosuppressive microenvironment by transcriptionally activating PD-L1 and TGFβ. These findings provide more insight into the role of TGFβ in CBF-AML, establishing it as a primary, tumor-derived immunosuppressor directly driven by the fusion oncogene. This provides a strong mechanistic rationale for incorporating TGFβ blockade into standard chemotherapy and immune checkpoint blockade regimens to restore anti-leukemic immunity and prevent relapse.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Stomatology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China",
    "Georgia Cancer Center, Augusta University, Augusta, Georgia, USA",
    "Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People's Republic of China",
    "Department of Medicine, Division of Hematology/Oncology, Augusta University, Augusta, Georgia, USA",
    "Department of Biochemistry and Molecular Biology, Augusta University Medical College of Georgia, Augusta, Georgia, USA",
    "Immunology Center of Georgia, Augusta University, Augusta, Georgia, USA",
    "Charlie Norwood VA Medical Center, Augusta, Georgia, USA",
    "Department of Biostatistics, Data Science and Epidemiology, Augusta University, Augusta, Georgia, USA",
    "Oncogenesis and Development Section, Division of Intramural Research, National Human Genome Research Institute, Bethesda, Maryland, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Hui Fang",
      "orcid": "0009-0008-3707-8414"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chang Liu",
      "orcid": "0009-0003-2010-8297"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiaocui Lu"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Ting Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xuexiu Fang"
    },
    {
      "affs": [
        1
      ],
      "name": "Stephanie F Mori"
    },
    {
      "affs": [
        1
      ],
      "name": "Miao Yu"
    },
    {
      "affs": [
        1
      ],
      "name": "Qimei Han"
    },
    {
      "affs": [
        1
      ],
      "name": "Yoonah Ruby"
    },
    {
      "affs": [
        1
      ],
      "name": "Gavin Wang"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Daniel Peters"
    },
    {
      "affs": [
        2
      ],
      "name": "Litao Zhang"
    },
    {
      "affs": [
        1,
        4,
        5
      ],
      "name": "Huidong Shi",
      "orcid": "0000-0003-1137-3390"
    },
    {
      "affs": [
        1,
        4,
        6
      ],
      "name": "Kebin Liu",
      "orcid": "0000-0003-1965-7240"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Jorge Cortes"
    },
    {
      "affs": [
        7
      ],
      "name": "Haocheng Ding"
    },
    {
      "affs": [
        8
      ],
      "name": "Paul Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Bo Cheng"
    },
    {
      "affs": [
        1,
        4,
        5
      ],
      "name": "TianXiang Hu",
      "orcid": "0000-0002-5127-9211"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0gnj943xeb09c.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-016242",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711591/",
  "id": "0gnj943xeb09c",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-016242",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "Basic and Translational Cancer Immunology"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2720|Acute Myeloid Leukemia Research"
    ]
  ],
  "openalex": "W7223695597",
  "pdf_url": null,
  "pmcid": "PMC13711591",
  "pmid": "42933890",
  "published": "2026-10-26",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/0gnj943xeb09c.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:20Z",
      "native_id": "PMC13711591",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-016242"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "journal-openalex:2403|Immunotherapy and Immune Responses",
      "subfield": "immunology"
    },
    {
      "field": "medicine",
      "origin": "journal-openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia",
  "title_text": "CBFB-MYH11 directly activates TGFβ and PD-L1 to drive immune evasion in acute myeloid leukemia",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:20Z",
  "url": "https://research.draconitic.com/paper/0gnj943xeb09c",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}