原发性骨髓纤维化（PMF）中前纤维化与明显纤维化的炎症、纤维化和免疫学特征差异

Different inflammatory, fibrotic, and immunological signatures between pre-fibrotic and overt primary myelofibrosis

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HAEMATOLOGICA

影响因子:7.9

分区:医学1区 Top / 血液学2区

发表日期:2025 Apr 01

作者: Seung-Hyun Jung, Sung-Eun Lee, Sujin Yun, Da-Eun Min, Youngjin Shin, Yeun-Jun Chung, Sug Hyung Lee

DOI: 10.3324/haematol.2024.285598

摘要

原发性骨髓纤维化（PMF）是一种由骨髓纤维化为特征的髓系增殖性肿瘤（MPN）。前纤维化PMF（pre-PMF）可进展为明显纤维化的PMF。巨核细胞在PMF中起主要作用，但不同巨核细胞亚群及其他造血细胞在PMF进展中的功能尚不清楚。因此，我们利用单细胞RNA测序分析了pre-PMF、明显纤维化PMF及其他MPN的骨髓采样。共鉴定出14种细胞类型及其亚群，包括造血干/祖细胞（HSPC）和巨核细胞。明显纤维化PMF中的HSPC表现出巨核细胞偏向性和炎症/纤维化富集。在巨核细胞中，富集上皮-间充质转化（EMT）特征的亚群在明显纤维化PMF中急剧增加。非纤维化/非PMF MPN中的巨核细胞富集于分化，而纤维化/非PMF MPN的巨核细胞则富集于炎症/纤维化。总体而言，从pre-PMF到明显纤维化PMF，HSPC、巨核细胞和CD14+单核细胞的炎症/纤维化标志物表达增强。细胞毒性和功能障碍评分在T细胞和NK细胞中也有所升高。临床方面，伴有高炎症/纤维化标志物的巨核细胞和HSPC亚群在外周血芽细胞≥1%的患者中更常见。单细胞RNA测序预测明显纤维化PMF中的巨核细胞分化、炎症/纤维化、免疫效应/功能障碍及肿瘤相关信号的细胞通讯明显增强，但在PMF进展过程中未发现决定性亚群。研究表明，HSPC、单核细胞和淋巴细胞在PMF的进展中起作用，且炎症/纤维化及免疫功能障碍存在亚群特异性。PMF的进展可能依赖于多种细胞类型的变化，富含EMT的巨核细胞可能成为诊断和治疗的潜在靶点。

Abstract

Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes play a primary role in PMF; however, the functions of megakaryocyte subsets and those of other hematopoietic cells during PMF progression remain unclear. We, therefore, analyzed bone marrow aspirates in cases of pre-PMF, overt PMF, and other MPN using single-cell RNA sequencing. We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPC) and megakaryocytes. HSPC in overt PMF were megakaryocyte-biased and inflammation/fibrosis-enriched. Among megakaryocytes, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. Megakaryocytes in non-fibrotic/non-PMF MPN were megakaryocyte differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, megakaryocyte, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, megakaryocyte and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. Single-cell RNA-sequencing predicted higher cellular communication of megakaryocyte differentiation, inflammation/fibrosis, immunological effector/dysfunction, and tumor-associated signaling in overt PMF than in pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPC, monocytes, and lymphoid cells contribute to the progression of PMF, and subset specificity existed regarding inflammation/fibrosis and immunological dysfunction. PMF progression may depend on alterations of multiple cell types, and EMT-enriched megakaryocytes may be potential targets for diagnosing and treating the progression.