Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7 MPL monocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.
Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.
Sudden blast phase (SBP) is a rare event in which patients with chronic myeloid leukemia (CML) in complete cytogenetic response (CCyR) rapidly progress to the blast phase. Few patients on second-generation tyrosine kinase inhibitors (2nd TKIs) have been reported to develop SBP. Here, we report a 45-year-old man diagnosed with CML in the chronic phase in April 2008 and immediately started on imatinib therapy. He achieved CCyR 12 months after starting imatinib therapy. Imatinib was followed by treatment with the 2nd TKIs nilotinib and dasatinib from January 2011 to yield a better response. He achieved major molecular response (MMR) during dasatinib therapy in February 2012, but did not tolerate dasatinib well; hence, he was switched to nilotinib in July 2012. In December 2015, he presented at our hospital with fever and lumbago. A complete blood count revealed a white blood cell count of 30,500/µL with 60% blasts, leading to diagnosis of SBP. After dasatinib therapy and conventional chemotherapy, he again achieved MMR. This case demonstrates that SBP may occur after achieving MMR on treatment with 2nd TKIs. Continuous careful monitoring is required for the early detection of SBP, even in patients who have achieved MMR.
Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Vα7.2+CD161+IL-18Rα+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4−CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4−CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4−CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4−CD8+ MAIT cells. In conclusion, total MAIT and CD4−CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone.
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