Vosbeck Karla, Förster Sarah, Mayr Thomas, Sahu Anshupa, Haddouti El-Mustapha, Al-Adilee Osamah, Körber Ruth-Miriam, Bisht Savita, Muders Michael H, Nesic Svetozar, Buness Andreas, Kristiansen Glen, Schildberg Frank A, Gütgemann Ines
Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany.
Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
Cancers (Basel). 2024 May 18;16(10):1924. doi: 10.3390/cancers16101924.
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 ( = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN ( < 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 JAK2 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 mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.
骨髓增殖性肿瘤（MPN）、骨髓增生异常综合征（MDS）、MPN/MDS重叠综合征及急性髓系白血病（AML）中的骨髓纤维化与预后不良及早期治疗失败相关。骨髓纤维化（MF）伴有多能骨髓间充质基质细胞（MSC）重编程为类骨质和纤维生成性基质细胞。通过免疫组织化学评估，我们证实在正常骨髓的骨内膜龛内有神经纤毛蛋白2（NRP2）和骨系标志物神经细胞黏附分子1（NCAM1）表达，而在MPN、MDS、MPN/MDS重叠综合征及AML（ = 99）中表达异常。间充质基质细胞和成骨细胞中NRP2和NCAM1表达增加及弥漫性表达与MPN中高MF分级相关（NRP2和NCAM1的 < 0.05）。单细胞RNA测序（scRNAseq）重新分析显示内皮细胞中有NRP2表达，正常MSC和成骨细胞中有NRP2和NCAM1部分共表达。潜在配体包括来自成骨细胞和巨核细胞的转化生长因子β1（TGFB1）。小鼠血小板生成素（ThPO）和JAK2骨髓纤维化模型显示骨系细胞中有Nrp2和Ncam1共表达，而促进纤维化的MSC仅表达Nrp2。对MC3T3-E1前成骨细胞进行的体外实验及对小鼠股骨的分析表明Nrp2在骨生成中起功能性作用。总之，NRP2是骨髓纤维化患者潜在的新型可成药靶点。
