Elucidating Mechanisms Underlying Fibrocyte-Mediated Myelofibrosis Induction in Myelodysplastic Syndromes

Background: The mechanism underlying myelofibrosis, which is associated with poor prognosis in myelodysplastic syndromes (MDS), remains unclear. Methods: We investigated the mechanisms underlying myelofibrosis using peripheral blood mononuclear cells (PBMCs) from healthy donors, MDS92 cell culture supernatants and PolgA/+ and PolgA/A mice treated with high-dose romiplostim as an MDS model. We used the LEGENDplex™ immunoassay to analyze cytokine levels in MDS92 culture supernatants and serum samples from 12 patients with MDS or acute myeloid leukemia with myelodysplasia-related cytogenetic abnormalities. Results: The MDS92 cell culture supernatants inhibited monocyte differentiation into fibrocytes and contained significantly lower levels of CXCL1 (C-X-C motif chemokine ligand 1), IL-6 (Interleukin-6), and CCL22 (C-C motif chemokine ligand 22) than PBMC culture supernatants from healthy donors. Among serum samples from patients with MDS, IL-18 level was positively correlated with myelofibrosis grade and splenomegaly. In PolgA/A mice, the F4/80high CD11blow/int cell fraction of the spleen was significantly increased following romiplostim administration, compared with PolgA/+ mice; however, worsening of splenomegaly was not observed. Furthermore, reticulin fibers were observed mainly in the subcortical region in all PolgA/+ mice but were rare in the PolgA/A mice. Conclusions: These findings suggest an association between altered cytokine signaling fibrocyte differentiation, and myelofibrosis in MDS. Further studies are required to clarify how cytokine levels and cellular responsiveness contribute to fibrocyte-mediated myelofibrosis.