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

Abstract

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.