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Abstract：
Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2V617F myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of Nrp2-/- mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.
摘要：
骨髓增殖性肿瘤（MPN）的骨髓纤维化，骨髓增生异常综合征（MDS），MPN/MDS重叠综合征与急性髓细胞性白血病（AML）预后差和早期治疗失败有关。骨髓纤维化（MF）伴随着多能骨髓间充质基质细胞（MSC）重新编程为类骨质和产生纤维的基质细胞。我们证明了正常骨髓和MPN异常中NRP2和骨骼系统标记物NCAM1（神经细胞粘附分子1）在内膜壁龛内的表达，MDSMPN/MDS重叠综合征和AML(n=99)，通过免疫组织化学评估。间充质基质细胞和成骨细胞中的增加和扩散表达与MPN中的高MF等级相关(对于NRP2和NCAM1,p<0.05)。单细胞RNA测序(scRNAseq)再分析表明NRP2在内皮细胞中表达,NRP2和NCAM1在正常MSC和成骨细胞中部分共表达。潜在的配体包括来自成骨细胞和巨核细胞的转化生长因子β1(TGFB1)。小鼠ThPO和JAK2V617F骨髓纤维化模型显示Nrp2和Ncam1在成骨细胞中共表达,而促进纤维化的MSC仅表达Nrp2。MC3T3-E1前成骨细胞的体外实验和Nrp2-/-小鼠股骨的分析表明Nrp2在功能上参与了成骨。总之,NRP2代表骨髓纤维化患者的潜在新型药物靶标。
