Bock Oliver, Muth Michaela, Theophile Katharina, Winter Melissa, Hussein Kais, Büsche Guntram, Kröger Nicolaus, Kreipe Hans
Institute of Pathology, Hannover Medical School, Hannover, Germany.
Br J Haematol. 2009 Sep;146(5):510-20. doi: 10.1111/j.1365-2141.2009.07808.x. Epub 2009 Jul 13.
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by remodelling of the bone marrow, including progressive myelofibrosis and exaggerated angiogenesis. Advanced PMF frequently shows a full-blown fibre meshwork, which avoids aspiration of cells, and the expression profile of genes related to stroma pathology at this stage remains largely undetermined. We investigated bone marrow core biopsies in PMF showing various degrees of myelofibrosis by custom-made low density arrays (LDA) representing target genes with designated roles in synthesis of extracellular matrix, matrix remodelling, cellular adhesion and motility. Among a set of 11 genes up-regulated in advanced stages of PMF (P < or = 0.01) three candidates, PTK2 protein tyrosine kinase 2 (PTK2), transforming growth factor beta type II receptor (TGFBR2) and motility-related protein-1 (CD9 molecule, CD9), were investigated in more detail. PTK2, TGFBR2 and CD9 were significantly overexpressed in larger series of advanced PMF stages (P < or = 0.01 respectively). Endothelial cells of the increased microvessel network in PMF could be identified as a predominant source for PTK2, TGFBR2 and CD9. CD9 also strongly identified activated fibroblasts in advanced myelofibrosis. We conclude that PTK2, TGFBR2 and CD9 represent new target molecules involved in bone marrow remodelling of PMF and warrant further investigation for potential targeted therapy.
原发性骨髓纤维化（PMF）是一种骨髓增殖性肿瘤，其特征为骨髓重塑，包括进行性骨髓纤维化和过度血管生成。晚期PMF常表现为成熟的纤维网络，这会妨碍细胞抽吸，且此阶段与基质病理相关的基因表达谱仍 largely 未确定。我们通过定制的低密度阵列（LDA）对显示不同程度骨髓纤维化的PMF患者的骨髓核心活检进行了研究，该阵列代表在细胞外基质合成、基质重塑、细胞黏附和运动中具有特定作用的靶基因。在一组在PMF晚期上调的11个基因中（P≤0.01），对三个候选基因，即蛋白酪氨酸激酶2（PTK2）、转化生长因子βⅡ型受体（TGFBR2）和运动相关蛋白1（CD9分子，CD9）进行了更详细的研究。PTK2、TGFBR2和CD9在更多晚期PMF阶段的样本中显著过表达（分别为P≤0.01）。PMF中微血管网络增加的内皮细胞可被确定为PTK2、TGFBR2和CD9的主要来源。CD9在晚期骨髓纤维化中也强烈识别活化的成纤维细胞。我们得出结论，PTK2、TGFBR2和CD9代表参与PMF骨髓重塑的新靶分子，值得进一步研究其潜在的靶向治疗作用。
