Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Abstract

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)

Clinical Correlates and Prognostic Significance of IL-8, sIL-2R, and Immunoglobulin-Free Light Chain Levels in Patients with Myelofibrosis

“…They promote the proliferation and osteoblastic differentiation of bone marrow stromal cells and induce the expression of cytokines such as vascular endothelial growth factor, transforming growth factor beta 1, osteoprotegerin, and collagen type I. The latter facilitates fibrosis and bone formation, and contributes to neoangiogenesis [13]. Other cytokines such as IL-8, IL-6, and IL-1β are also overexpressed by malignant MPN cells and can cause activation of normal inflammatory cells [14].…”

Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

“…24 Lipocalin-2 is a potent inflammatory cytokine that is markedly elevated in the plasma of patients with MPN (particularly MF) and has been shown to preferentially promote proliferation of MF CD34 + cells, induce breaks in double-stranded DNA and cause apoptosis of normal bone marrow cells, as well as enhance stromal cell proliferation through the production of reactive oxygen species. 26 A lipocalin-2-induced increase in the expression of the extracellular matrix protein collagen type 1 (COL1A1) by mesenchymal stem cells as well as other disturbances in the bone marrow microenvironment likely contribute to the progression of the malignant HSC.…”

The spleen of patients with myelofibrosis harbors defective mesenchymal stromal cells

“…Whether the mutated HSPC is responsible of the MSC damage, or vice versa, remains to be clarified. However, recent observations seem to suggest that a damage of the microenvironment and in particular of MSCs could be exerted by the malignant hematopoietic cells through the release of molecules such as IL1‐beta or lipocalin, perpetuating a vicious circle in which mutated hematopoietic cells impair the function of MSCs which in turn are not any longer able to correctly modulate a normal function of hematopoiesis.…”