Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Bioinformatics Institute, Seoul National University, Seoul, Republic of Korea.
Cancer Med. 2024 Sep;13(18):e70238. doi: 10.1002/cam4.70238.
Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background.
Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed.
A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV.
In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function.
溶酶体功能障碍（LD）会影响细胞因子的调节、炎症和免疫反应，从而影响癌症的发生和发展。炎症与骨髓增殖性肿瘤（MPN）的发病机制有关。我们假设 LD 通过诱导异常炎症显著促进 MPN 的致癌作用，因此我们的目的是阐明源于 LD 背景的 MPN 的病理生理机制。
对一组 MPN 患者（n=190）和健康对照（n=461）进行 LD 背景的基因分型。使用基因型数据进行逻辑回归建模，以估计 LD 与 MPN 之间的相关性。生成并分析了全转录组测序（WTS）（LD 携带者=8，非携带者=6）和单细胞 RNA 测序数据（LD 携带者=2，非携带者=2，健康对照=2）。
与健康对照相比，MPN 中 LD 的变异频率更高（健康对照为 4.9%，MPN 为 7.8%），其中 PV 中的频率最高（优势比=2.33，p=0.03）。WTS 显示，与非携带者相比，LD 携带者的 MPN 中炎症细胞因子配体-受体基因、途径和网络模块上调。在单细胞水平上，存在单核细胞扩增和细胞因子配体-受体相互作用、炎症转录因子以及以单核细胞为中心的网络模块的升高。值得注意的是，Oncostatin-M（OSM）一直被认为是参与 LD 相关 PV 发病机制的候选分子。
总之，LD 背景在 MPN 患者中很常见，导致细胞因子失调和炎症增加。OSM 作为潜在分子之一，通过损害溶酶体功能在 PV 发病机制中起关键作用。
