对间充质细胞的全面分析表明,骨髓纤维化患者体内的 TGF-β/Wnt/HOXB7 轴失调。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-29 DOI:10.1172/jci.insight.173665
Saravanan Ganesan, Sarah Awan-Toor, Fabien Guidez, Nabih Maslah, Rifkath Rahimy, Céline Aoun, Panhong Gou, Chloé Guiguen, Juliette Soret, Odonchimeg Ravdan, Valeria Bisio, Nicolas Dulphy, Camille Lobry, Marie-Hélène Schlageter, Michèle Souyri, Stéphane Giraudier, Jean-Jacques Kiladjian, Christine Chomienne, Bruno Cassinat
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引用次数: 0

摘要

尽管对骨髓增生性肿瘤(MPN)的认识和治疗取得了进展,但这种疾病仍然无法治愈,并有可能演变为急性髓细胞性白血病(AML)或骨髓纤维化(MF)。遗憾的是,人们对该病向骨髓纤维化演变的过程仍然知之甚少,这阻碍了预防和治疗方案的选择。最近对实体瘤微环境和器官纤维化的研究有助于深入了解它们各自的发病机制和耐药性,但在骨髓增生性疾病中却缺乏此类精确数据。在本研究中,我们通过对患者样本驱动的间充质干细胞微环境转录组学和表观遗传学描述以及基于细胞的分析,确定了 HOXB7 的过表达,更准确地说,是一种新型的 TGFβ-Wnt-HOXB7 通路,它与间充质基质细胞(MSCs)的促纤维化和促成骨细胞偏向分化有关。通过对该通路的基因抑制和化学抑制,我们逆转了骨髓纤维化患者间充质干细胞的异常表型,为骨髓增生性疾病领域提供了一个潜在的新靶点,以预防和控制向骨髓纤维化的演变。
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Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/Wnt/HOXB7 axis in patients with myelofibrosis.

Despite the advances in the understanding and treatment of myeloproliferative neoplasm (MPN), the disease remains incurable with the risk of evolution to AML or myelofibrosis (MF). Unfortunately, the evolution of the disease to MF remains still poorly understood impeding preventive and therapeutic options. Recent studies in solid tumor microenvironment and organ fibrosis have shed instrumental insights on their respective pathogenesis and drug resistance, yet such precise data are lacking in MPN. In this study, through a patient-sample driven transcriptomic and epigenetic description of the MF microenvironment landscape and cell-based analyses, we identify HOXB7 overexpression and more precisely a novel TGFβ-Wnt-HOXB7 pathway as associated to a pro-fibrotic and pro-osteoblastic biased differentiation of mesenchymal stromal cells (MSCs). Using gene-based and chemical inhibition of this pathway we reverse the abnormal phenotype of MSCs from myelofibrosis patients, providing the MPN field with a potential novel target to prevent and manage evolution to MF.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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