Key Points• LCN2 acts to generate reactive oxygen species, leading to increased DNA strand breaks and apoptosis in normal CD34 1 cells.• LCN2 promotes the generation of osteoblasts but diminishes adipogenesis, resembling the composition of the MF marrow microenvironment.Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34 1 cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. (Blood. 2015;126(8):972-982)

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Risk stratification of patients with essential thrombocythemia/polycythemia vera by age and/or history of thrombosis provides the basis of risk adapted therapeutic intervention. Aggressive control of modifiable cardiovascular risk factors, the use of antiplatelet agents, control of the hematocrit less than 45% in polycythemia vera, and cytoreductive therapy in high-risk essential thrombocythemia/polycythemia vera patients is the focus of management. The exact role of IFN-α remains undefined and under active investigation, and the recent approval of ruxolitinib provides patients with polycythemia vera a second-line option.

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