Yu Helena, Signer Robert A J
Department of Pediatric Hematology/Oncology, Rady Children's Hospital-San Diego, San Diego, CA.
Division of Hematology/Oncology, Department of Pediatrics, University of California San Diego, La Jolla, CA.
Blood. 2025 Jul 17;146(3):304-317. doi: 10.1182/blood.2024024956.
Inherited bone marrow failure syndromes (IBMFS) are genetic disorders of impaired hematopoiesis that manifest in childhood with both cytopenias and extrahematologic findings. Although several IBMFS are categorized as ribosomopathies owing to shared underlying ribosomal dysfunction, there is a broader disruption of the protein homeostasis (proteostasis) network across both classic and emerging IBMFS. Precise regulation of the proteostasis network, including mechanisms of protein synthesis, folding, trafficking, and degradation and associated stress response pathways, has emerged as essential for maintaining hematopoietic stem cell function, providing new potential mechanistic insights into IBMFS pathogenesis. Furthermore, the varied clinical trajectories of patients with IBMFS with possible divergent outcomes of malignancy and spontaneous remission may reflect developmental and temporal changes in proteostasis activity and be driven by strong selective pressures to restore proteostasis. These new insights are spurring fresh therapeutic approaches to target proteostasis. Thus, further evaluation of proteostasis regulation and the consequences of proteostasis disruption in IBMFS could aid in developing new biomarkers, therapeutic agents, and preventive approaches for patients.
遗传性骨髓衰竭综合征（IBMFS）是造血功能受损的遗传性疾病，在儿童期表现为血细胞减少和血液外表现。尽管由于共同的潜在核糖体功能障碍，几种IBMFS被归类为核糖体病，但在经典和新出现的IBMFS中，蛋白质稳态（蛋白稳态）网络存在更广泛的破坏。蛋白稳态网络的精确调控，包括蛋白质合成、折叠、运输和降解机制以及相关的应激反应途径，已成为维持造血干细胞功能的关键，为IBMFS发病机制提供了新的潜在机制见解。此外，IBMFS患者不同的临床病程，可能有不同的恶性肿瘤和自发缓解结果，这可能反映了蛋白稳态活性的发育和时间变化，并受到恢复蛋白稳态的强大选择压力的驱动。这些新见解正在催生出针对蛋白稳态的新治疗方法。因此，进一步评估IBMFS中蛋白稳态调控及其破坏的后果，可能有助于为患者开发新的生物标志物、治疗药物和预防方法。
