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<p>Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of <i>Osm</i> in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6–JAK–STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.</p>

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Oncostatin M induced by STAT5-activating oncogenes promotes disease progression in hematologic malignancies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Michael Rassner,
  • Tony Andreas Müller,
  • Kirstyn Anne Crossley,
  • Geoffroy Andrieux,
  • Sabina Schaberg,
  • Cornelia Endres,
  • Lena Jakob,
  • Teresa Poggio,
  • Natalie Köhler,
  • Julia Kolter,
  • Gerhard Müller-Newen,
  • Katharina Schönberger,
  • Nina Cabezas-Wallscheid,
  • Irene Gonzalez-Menendez,
  • Leticia Quintanilla-Martinez,
  • Melissa Zwick,
  • Driti Ashok,
  • Tanja Nicole Hartmann,
  • Olaf Groß,
  • Oliver Gorka,
  • Marie Follo,
  • Anna Lena Illert,
  • Melanie Boerries,
  • Robert Zeiser,
  • Justus Duyster

摘要

Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6–JAK–STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.