Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
Department of Malignant Hematology, and.
Blood Adv. 2021 Apr 27;5(8):2216-2228. doi: 10.1182/bloodadvances.2020003475.
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)-inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death.
骨髓增生异常综合征（MDS）是异质性造血干细胞恶性肿瘤，其表型可能类似于其他血液系统疾病。因此，能够辅助当前诊断实践的工具可能有助于疾病鉴别。固有免疫的组成性激活是 MDS 无效造血的发病驱动因素，其通过 Nod 样受体蛋白 3（NLRP3）-炎症小体诱导的细胞焦亡性死亡。细胞裂解时会释放氧化的线粒体 DNA（ox-mtDNA），作为危险信号，通过 DNA 传感器触发炎症小体寡聚化。通过使用常见 MDS 体细胞基因突变的小鼠模型和 MDS 原发性样本的永生化骨髓细胞，我们证明细胞焦亡时会释放 ox-mtDNA。与健康供体的血浆相比，MDS 外周血（PB）血浆中的 ox-mtDNA 明显增加，并且在低危 MDS 中明显高于高危 MDS，这与低危患者中更多的细胞焦亡细胞分数一致。此外，与研究的所有其他血液系统恶性肿瘤相比，MDS PB 血浆中的 ox-mtDNA 明显更高，除慢性淋巴细胞白血病（CLL）外。接受者操作特征/曲线下面积（ROC/AUC）分析表明，与健康供体相比，ox-mtDNA 是 MDS 患者的敏感和特异性生物标志物（AUC，0.964），与除 CLL 之外的所有其他血液系统恶性肿瘤（AUC，0.893）和反应性疾病（AUC，0.940）相比。ox-mtDNA 与已知警报素 S100A9、S100A8 和凋亡相关斑点样蛋白含有半胱氨酸天冬氨酸蛋白酶募集域（CARD）斑点的水平呈正相关且显著相关，这些指标提供了骨髓细胞焦亡的指数。总的来说，这些数据表明，在炎症小体激活时释放到细胞外空间的可定量 ox-mtDNA 可作为 MDS 的生物标志物，以及细胞焦亡性死亡的程度。
