MYC-Alarmin Axis as a Novel Therapeutic Vulnerability in Triple Negative Myeloproliferative Neoplasms

Despite advances in our understanding of the underlying genetic abnormalities in myelofibrosis (MF) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly in triple negative MF patients who lack mutations in the JAK2 kinase pathway. Here we report that MYC copy number gain (e.g., trisomy 8) is frequently identified in triple negative MF where MF development and progression rely on MYC-directed activation of S100A9, a Danger Associated Molecular Pattern (DAMP) protein that plays pivotal roles in inflammation. Notably, MYC-S100A9 axis underlies complex network of inflammatory signaling that involves various hematopoietic cell types in the bone marrow microenvironment. Accordingly, small molecules targeting the MYC-S100A9 pathway effectively ameliorated the MF phenotypes, highlighting MYC-alarmin axis as a novel therapeutic vulnerability in a subgroup of MF patients. The goal of this study is to compare gene expression profiles in hematopoietic cellsl in bone marrow following overexpression of MYC in hematopoietic stem cells.尽管我们对骨髓纤维化（myelofibrosis, MF）的潜在遗传异常及JAK2抑制剂的研发已取得一定进展，但目前仍迫切需要开发全新的治疗策略，尤其是针对JAK2激酶通路未发生突变的三阴性骨髓纤维化患者群体。本研究报道，MYC拷贝数增加（如8号染色体三体）在三阴性骨髓纤维化中频繁检出；此类骨髓纤维化的发生与进展，依赖于MYC介导的S100A9激活——S100A9是一类在炎症反应中发挥核心作用的损伤相关分子模式（Damage Associated Molecular Pattern, DAMP）蛋白。值得关注的是，MYC-S100A9轴构成了复杂的炎症信号网络，该网络涵盖骨髓微环境中的多种造血细胞类型。实验结果显示，靶向MYC-S100A9通路的小分子化合物可有效改善骨髓纤维化表型，这表明MYC-警报素轴可作为特定骨髓纤维化患者亚群的新型治疗易感靶点。本研究的目标为比较造血干细胞（hematopoietic stem cells）过表达MYC后，骨髓内造血细胞的基因表达谱。