Increased SLAMF7(high) monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab

摘要

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 SLAMF7(high) monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7(high) monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, andMPNpatients withoutMFby using a cross-sectional approach. Wefound thatMPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7(high) 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 SLAMF7(high) monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7(high) monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7(high) monocytes was significantly higher than that of SLAMF7(low) 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 fromMFpatients in vitro. Elo also amelioratedMFand splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7(high) 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.