{
  "abstract": "Myelofibrosis (MF) is characterized by chronic inflammation, progressive bone marrow fibrosis, and impaired immune surveillance. Although natural killer (NK) cell dysfunction has been described in myeloproliferative neoplasms (MPN), its relationship with MF severity and the contribution of the malignant microenvironment remain poorly defined. We hypothesized that progressive MF induces an NK-cell maturation defect driven by the MPN microenvironment and differentially affected by JAK1/2 versus selective JAK2 inhibition. We evaluated 31 untreated patients with MF and 9 healthy donors (HD). Patients were stratified by fibrosis grade, DIPSS-plus risk, and driver mutation. Peripheral blood NK-cell subsets, maturation, and activating/inhibitory receptors were characterized by multiparametric flow cytometry, and cytotoxicity against K562 cells. To validate these findings, we examined chimeric murine models in which genetically normal NK cells developed in either Jak2V617F (Jak2VF) non-fibrotic or MplW515L (Mpl) fibrotic MPN environments. NK-cell responsiveness to inflammatory stimulation was assessed following poly(I:C) challenge. The effects of JAK1/2 inhibition with ruxolitinib and selective JAK2 inhibition with fedratinib were subsequently compared in vivo. MF patients displayed preserved total NK-cell frequency but impaired maturation, characterized by a reduced CD56dim/CD56bright ratio, decreased mature CD11b single-positive (SP) cells, and expansion of immature NK subsets. NKp80 and NKG2D activating receptors expression were markedly reduced, accompanied by impaired K562 cytotoxicity measured by specific NK-mediated cell death assay. NK-cell abnormalities increased with disease severity: patients with intermediate-2/high DIPSS-plus risk exhibited a significantly lower CD56dim/CD56bright ratio, and logistic regression confirmed its association with high-risk disease. Both Jak2VF and Mpl chimeric models demonstrated impaired NK-cell maturation. The findings were present in non-MPN cells, demonstrating that the MPN microenvironment is sufficient to recapitulate this phenotype. The defect was most pronounced in fibrotic Mpl disease, with accumulation of NK progenitors and loss of mature NK cells. Mature NK cells inversely correlated with splenomegaly and positively correlated with hemoglobin and were significantly reduced in animals with advanced fibrosis. NKG2D was also reduced in both MPN models. Following poly(I:C) stimulation, MPN-exposed NK cells retained cytokine responsiveness but failed to restore NKG2D expression, indicating persistent impairment despite inflammatory activation. JAK inhibition differentially affected this pre-existing immune defect. Ruxolitinib further impaired NK-cell maturation, reducing mature CD11b SP NK cells in both Jak2F and Mpl models. In contrast, fedratinib exerted a more limited effect and preserved mature NK-cell frequencies in fibrotic Mpl disease. These findings identify impaired NK-cell maturation as a hallmark of MF severity that is imposed by the malignant microenvironment and persists despite inflammatory stimulation. Moreover, dual JAK1/2 inhibition further exacerbated NK-cell dysfunction, whereas selective JAK2 inhibition had a less detrimental effect on NK-cell homeostasis. NK-cell maturation may therefore represent both a biomarker of MF progression and an immunological consideration when selecting JAK-targeted therapies.",
  "abstract_shown": true,
  "affiliations": [
    "Regional Blood Center of Ribeirao Preto, USP, Ribeirão Preto, SP, Brasil",
    "QIMR Berghofer, Australia",
    "Hematology, Hemotherapy and Cell Therapy Division, Department of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical School, USP, Ribeirão Preto, SP, Brazil",
    "QIMR Berghofer, Austria"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mariana Mariana MEDEIROS"
    },
    {
      "affs": [
        0
      ],
      "name": "Allana CARVALHO"
    },
    {
      "affs": [
        1
      ],
      "name": "Alban JOHANSSON"
    },
    {
      "affs": [
        0
      ],
      "name": "Larissa Sarri BINELLI"
    },
    {
      "affs": [
        0
      ],
      "name": "Camila GARCIA"
    },
    {
      "affs": [
        0
      ],
      "name": "Isabela Catarin ARRUDA"
    },
    {
      "affs": [
        0
      ],
      "name": "Beatriz ADJAFRE"
    },
    {
      "affs": [
        0
      ],
      "name": "Leticia MARANI"
    },
    {
      "affs": [
        2
      ],
      "name": "Priscila SCHEUCHER"
    },
    {
      "affs": [
        2
      ],
      "name": "Josiane Lilian dos Santos SCHIAVINATO"
    },
    {
      "affs": [
        0
      ],
      "name": "Cleide Lúcia ARAUJO"
    },
    {
      "affs": [
        3
      ],
      "name": "Emily COOPER"
    },
    {
      "affs": [
        1
      ],
      "name": "Natalie CHAN"
    },
    {
      "affs": [
        2
      ],
      "name": "Rafael PACCA"
    },
    {
      "affs": [
        2
      ],
      "name": "Leonardo PALMA"
    },
    {
      "affs": [
        1
      ],
      "name": "Megan BYWATER"
    },
    {
      "affs": [
        1
      ],
      "name": "Steven W LANE"
    },
    {
      "affs": [
        0
      ],
      "name": "Lorena Lobo FIGUEIREDO-PONTES"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fpskt5h5dm26v.bib",
  "cited_by": 0,
  "doi": "10.1016/j.htct.2026.107540",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2531137926012873",
  "id": "fpskt5h5dm26v",
  "issns": [
    "2531-1379",
    "2531-1387"
  ],
  "landing_url": "https://doi.org/10.1016/j.htct.2026.107540",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC633-647.5"
    ],
    [
      "openalex",
      "2403|Immune Cell Function and Interaction"
    ]
  ],
  "openalex": "W7223086510",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/fpskt5h5dm26v.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:43:28Z",
      "native_id": "e9bb1007895a434aaae0acba9492b4b7",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.htct.2026.107540"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune Cell Function and Interaction",
      "subfield": "immunology"
    }
  ],
  "title": "THE MPN MICROENVIRONMENT DRIVES NK-CELL MATURATION DEFECTS ASSOCIATED WITH HIGH-RISK DISEASE",
  "title_text": "THE MPN MICROENVIRONMENT DRIVES NK-CELL MATURATION DEFECTS ASSOCIATED WITH HIGH-RISK DISEASE",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:28Z",
  "url": "https://research.draconitic.com/paper/fpskt5h5dm26v",
  "venue": "Hematology, Transfusion and Cell Therapy",
  "versions": []
}