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

IF 8.2 1区 医学 Q1 HEMATOLOGY
Seung-Hyun Jung, Sung-Eun Lee, Sujin Yun, Da-Eun Min, Youngjin Shin, Yeun-Jun Chung, Sug Hyung Lee
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引用次数: 0

Abstract

Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow (BM) fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes (MKs) play a primary role in PMF; however, the functions of MK subsets and those of other hematopoietic cells during PMF progression remain unclarified. Therefore, we analyzed BM aspirates in pre-PMFs, overt PMFs, and other MPNs using single-cell RNA sequencing (scRNA-seq). We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPCs) and MKs. HSPCs in overt PMF were MK-biased and inflammation/fibrosis-enriched. Among MKs, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. MKs in non-fibrotic/non-PMF MPN were MK differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, MK, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, MK and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. scRNA-seq predicted higher cellular communications of MK differentiation, inflammation/fibrosis, immunologic effector/dysfunction, and tumor-associated signaling in overt PMF than pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPCs, monocytes, and lymphoid cells contribute to PMF progression, and subset specificity existed regarding inflammation/fibrosis and immunologic dysfunction. PMF progression may depend on multiple cell types' alterations, and EMTenriched MKs may be potential targets for the diagnosis and therapy of the progression.

纤维化前期和原发性骨髓纤维化之间存在不同的炎症、纤维化和免疫学特征。
原发性骨髓纤维化(PMF)是一种以骨髓(BM)纤维化为特征的骨髓增殖性肿瘤(MPN)。纤维化前骨髓纤维化(pre-PMF)会发展为明显的骨髓纤维化。巨核细胞(MK)在原发性骨髓纤维化中起主要作用;然而,巨核细胞亚群和其他造血细胞在原发性骨髓纤维化进展过程中的功能仍未明确。因此,我们利用单细胞 RNA 测序(scRNA-seq)分析了前骨髓增生性疾病、显性骨髓增生性疾病和其他骨髓增生性疾病的骨髓穿刺液。我们确定了14种细胞类型及其亚群,包括造血干细胞和祖细胞(HSPCs)以及MKs。显性 PMF 中的 HSPCs 以 MK 为基础,并富含炎症/纤维化。在MKs中,上皮-间质转化(EMT)富集亚群在显性PMF中突然增加。非纤维化/非PMF MPN中的MK富含MK分化,而纤维化/非PMF MPN中的MK富含炎症/纤维化。总体而言,从PMF前期到明显的PMF,HSPC、MK和CD14+单核细胞亚群的炎症/纤维化特征有所增加。T细胞和NK细胞的细胞毒性和功能障碍评分也有所增加。scRNA-seq预测,在显性PMF中,MK分化、炎症/纤维化、免疫效应/功能障碍和肿瘤相关信号转导的细胞通讯量高于PMF前。然而,PMF进展过程中并没有出现决定性的亚群。我们的研究表明,HSPCs、单核细胞和淋巴细胞有助于PMF的进展,而在炎症/纤维化和免疫功能障碍方面存在亚群特异性。PMF的进展可能取决于多种细胞类型的改变,而富含EMT的MKs可能是诊断和治疗PMF进展的潜在靶点。
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来源期刊
Haematologica
Haematologica 医学-血液学
CiteScore
14.10
自引率
2.00%
发文量
349
审稿时长
3-6 weeks
期刊介绍: Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research. Scope: The scope of the journal includes reporting novel research results that: Have a significant impact on understanding normal hematology or the development of hematological diseases. Are likely to bring important changes to the diagnosis or treatment of hematological diseases.
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