纤维化和明显的原发性骨髓纤维化之间的不同炎症，纤维化和免疫学特征
Different inflammatory, fibrotic, and immunological signatures between pre-fibrotic and overt primary myelofibrosis
影响因子:7.90000
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
摘要
原发性骨髓纤维化（PMF）是以骨髓纤维化为特征的髓样增殖性肿瘤（MPN）。纤维化PMF（PRE-PMF）发展为明显的PMF。巨核细胞在PMF中起主要作用；然而，巨核细胞亚群和PMF进展过程中其他造血细胞的功能尚不清楚。因此，我们使用单细胞RNA测序分析了PRE-PMF，PART PMF和其他MPN的骨髓抽吸物。我们确定了14种具有亚群的细胞类型，包括造血茎和祖细胞（HSPC）和巨核细胞。公开PMF中的HSPC是巨核细胞偏置的，并富含炎症/纤维化。在巨核细胞中，在明显的PMF中突然增加了上皮 - 间质转变（EMT）富集的子集。非纤维化/非PMF MPN中的巨核细胞富含巨核细胞分化，而纤维化/非PMF MPN的巨核细胞则富含炎症/纤维化。总体而言，HSPC，Megakaryocyte和CD14+单核细胞子集的炎症/纤维化特征从PRE-PMF到明显的PMF增加。 T和NK细胞中的细胞毒性和功能障碍分数也增加。在临床上，外周血爆炸患者经常出现高炎症/纤维化特征的巨核细胞和HSPC亚群。单细胞RNA测序预测明显PMF中巨核细胞分化，炎症/纤维化，免疫效应子/功能障碍和肿瘤相关信号的较高的细胞通信比在PERPF前的PREF中更高。但是，在PMF进展过程中未出现决定性的子集。我们的研究表明，HSPC，单核细胞和淋巴样细胞有助于PMF的进展，并且在炎症/纤维化和免疫功能障碍方面存在子集特异性。 PMF的进展可能取决于多种细胞类型的改变，并且富含EMT的巨核细胞可能是诊断和治疗进展的潜在靶标。
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.