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<p>Constitutive JAK/STAT pathway activation is crucial in the pathogenesis of BCR::ABL1-negative&#xa0;myeloproliferative neoplasms (MPN), but has not yet been linked to interferon (IFN)-γ signaling and tumor microenvironment. Human <i>JAK2</i> V617F-mutated cell lines, 265 bone marrow biopsies (BMB) of two MPN cohorts, and 50 non-neoplastic BMB, revealed an intrinsic activation of IFN-γ signaling, which was confirmed by public RNA expression data. In vitro analysis of <i>JAK2</i>-mutated cell lines showed an activation of IFN-γ signaling pathway in the absence of IFN-γ in the cell supernatants. In addition, a heterogeneous, but increased expression of IFN-γ signaling components was found in BMB of <i>JAK2</i>-mutated samples with the highest expression in lymphocytes and monocytes, accompanied by increased tumor infiltrating lymphocytes (TIL). Unsupervised clustering identified a prognostic favorable cluster in both patient cohorts characterized by augmented IFN-γ signaling and TILs. This cluster was enriched with <i>JAK2</i>-mutated, JAK-inhibition naive MPN, mainly essential thrombocythemia and polycythemia vera with mild bone marrow fibrosis. Moreover, in silico data confirmed the link between <i>JAK2</i> mutations and increased IFN-γ signaling. Multivariate Cox regression revealed TILs to be the strongest prognostic marker. In conclusion, <i>JAK2</i>-mutated MPN exhibit an intrinsic activation of IFN-γ signaling associated with changes in the BM TME and patients’ outcome.</p><p></p>

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Association of the composition of the bone marrow tumor microenvironment in BCR::ABL1-negative myeloproliferative neoplasms with IFN-γ signaling and driver mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月5日

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  • Marcus Bauer,
  • Christoforos Vaxevanis,
  • Nadja Jaekel,
  • Hubert Hackl,
  • Andreas Wilfer,
  • Clara Zoellig,
  • Monika Haemmerle,
  • Carsten Müller-Tidow,
  • Haifa Kathrin Al-Ali,
  • Barbara Seliger,
  • Claudia Wickenhauser

摘要

Constitutive JAK/STAT pathway activation is crucial in the pathogenesis of BCR::ABL1-negative myeloproliferative neoplasms (MPN), but has not yet been linked to interferon (IFN)-γ signaling and tumor microenvironment. Human JAK2 V617F-mutated cell lines, 265 bone marrow biopsies (BMB) of two MPN cohorts, and 50 non-neoplastic BMB, revealed an intrinsic activation of IFN-γ signaling, which was confirmed by public RNA expression data. In vitro analysis of JAK2-mutated cell lines showed an activation of IFN-γ signaling pathway in the absence of IFN-γ in the cell supernatants. In addition, a heterogeneous, but increased expression of IFN-γ signaling components was found in BMB of JAK2-mutated samples with the highest expression in lymphocytes and monocytes, accompanied by increased tumor infiltrating lymphocytes (TIL). Unsupervised clustering identified a prognostic favorable cluster in both patient cohorts characterized by augmented IFN-γ signaling and TILs. This cluster was enriched with JAK2-mutated, JAK-inhibition naive MPN, mainly essential thrombocythemia and polycythemia vera with mild bone marrow fibrosis. Moreover, in silico data confirmed the link between JAK2 mutations and increased IFN-γ signaling. Multivariate Cox regression revealed TILs to be the strongest prognostic marker. In conclusion, JAK2-mutated MPN exhibit an intrinsic activation of IFN-γ signaling associated with changes in the BM TME and patients’ outcome.