Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab
Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab
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DOI：
10.1182/blood.2019000051
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发表时间：
2019-09-05
期刊：
影响因子：
20.3
通讯作者：
Kimura, Fumihiko
中科院分区：
文献类型：
--
作者：
Maekawa, Takaaki;Kato, Shoichiro;Kimura, Fumihiko
单核细胞来源的纤维细胞最近引起了人们的关注，因为骨髓纤维化（MF）的新发病机制，血清淀粉样蛋白P抑制纤维细胞分化显著改善MF。我们之前发现，与巨噬细胞相比，人纤维细胞高度表达信号淋巴细胞激活分子F7(SLAMF7)，并且MF患者外周血（PB）中的SLAMF7（高）单核细胞相对于健康对照（hc）显著升高。在这项研究中，我们使用横断面方法评估了肝癌、骨髓增生性肿瘤（MPN）伴MF患者和MPN伴mfs患者的PB中SLAMF7（高）单核细胞百分比。我们发现携带JAK2V617F的mpn MF患者具有显著升高的SLAMF7（高）单核细胞百分比，这与JAK2V617F等位基因负荷呈正相关。此外，血清白细胞介素-1ra （IL-1ra）浓度与SLAMF7（高）单核细胞百分比和JAK2V617F等位基因负荷显著相关。这些发现表明，SLAMF7（高）单核细胞和IL-1ra都可能是MF发病的有用的非侵入性标志物。此外，SLAMF7（高）单核细胞的JAK2V617F等位基因负荷显著高于SLAMF7（低）单核细胞，可能是elotuzumab （Elo）的潜在靶点，Elo是一种用于治疗多发性骨髓瘤的抗SLAMF7抗体。在体外，Elo不仅能独立抑制来自hcc的纤维细胞的分化，还能抑制来自mmf患者的纤维细胞的分化。Elo还能改善人源化NOG小鼠的mfand和罗米普洛斯汀诱导的脾肿大。综上所述，携带JAK2V617F的MPN患者中，携带较高JAK2V617F等位基因的SLAMF7（高）单核细胞的增加与MF发病有关，Elo可能是携带JAK2V617F的MPN MF患者的治疗剂。
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.