8 三体综合征定义了由 MYC-Alarmin 轴驱动的骨髓增殖性肿瘤的一个独特亚型。

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-07-01 DOI:10.1158/2643-3230.BCD-23-0210
Nicole D Vincelette, Xiaoqing Yu, Andrew T Kuykendall, Jungwon Moon, Siyuan Su, Chia-Ho Cheng, Rinzine Sammut, Tiffany N Razabdouski, Hai V Nguyen, Erika A Eksioglu, Onyee Chan, Najla Al Ali, Parth C Patel, Dae H Lee, Shima Nakanishi, Renan B Ferreira, Elizabeth Hyjek, Qianxing Mo, Suzanne Cory, Harshani R Lawrence, Ling Zhang, Daniel J Murphy, Rami S Komrokji, Daesung Lee, Scott H Kaufmann, John L Cleveland, Seongseok Yun
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引用次数: 0

摘要

尽管人们对骨髓增殖性肿瘤(MPNs)基因异常的认识取得了进展,并且开发出了 JAK2 抑制剂,但目前仍迫切需要制定新的治疗策略,尤其是针对三阴性骨髓纤维化(MF)患者,这些患者缺乏 JAK2 激酶通路中的突变,临床预后极差。我们在此报告,MYC拷贝数增殖和MYC表达增加经常发生在三阴性骨髓纤维化患者中,而MYC对S100A9(一种在炎症和先天免疫中发挥关键作用的警报蛋白)的定向激活是推动骨髓纤维化发展和进展的必要且充分条件。值得注意的是,MYC-S100A9回路引发了复杂的炎症信号转导网络,涉及骨髓微环境中的多种造血细胞类型。因此,对 S100A9 进行基因消融或使用靶向 MYC-S100A9 通路的小分子药物治疗可有效改善 MF 表型,从而凸显出 MYC-armin 轴是这一 MPN 亚群的新型治疗漏洞。
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Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.

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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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