Department of Medicine, University of Verona, Italy.
Unit of Immunology and Immunotherapy, Centro Ricerca Tettamanti, Pediatric Department, University of Milano Bicocca, Fondazione MBBM, Italy.
Am J Hematol. 2018 Aug;93(4):527-536. doi: 10.1002/ajh.25025. Epub 2018 Feb 9.
Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably, we show that ataluren treatment readily restores SBDS protein expression in different cell types, particularly bone marrow stem cells. Furthermore, ataluren promotes myeloid differentiation in hematopoietic progenitors, reduces apoptotic rate in primary PBMCs, and brings mammalian target of rapamycin phosphorylation levels back to normal in both lymphoblasts and bone marrow mesenchymal stromal cells (BM-MSCs). Since a specific therapy against SDS is currently lacking, these results provide the rationale for ataluren repurposing clinical trials.
Shwachman-Diamond 综合征（SDS）是一种罕见的遗传性隐性疾病，主要由 Shwachman-Bodian-Diamond 综合征（SBDS）基因突变引起，该基因编码同名蛋白 SBDS，其功能仍有待充分确定。SDS 影响多个器官，导致骨髓衰竭、外分泌胰腺功能不全、骨骼畸形和认知障碍。大约 15%的 SDS 患者会发展为骨髓增生异常综合征（MDS），并面临更高的急性髓系白血病（AML）风险。SBDS 表达的缺乏与骨髓造血祖细胞中的凋亡增加和髓系分化缺乏有关。重要的是，大多数 SDS 患者的 SBDS 携带无义突变。由于 ataluren 是一种经过充分研究的小分子抑制剂，可以抑制无义突变，因此，我们在这里评估了该药物在恢复从 SDS 患者队列中获得的造血细胞中 SBDS 表达方面的疗效。值得注意的是，我们表明，ataluren 治疗可轻易恢复不同细胞类型，特别是骨髓干细胞中的 SBDS 蛋白表达。此外，ataluren 可促进造血祖细胞中的髓系分化，降低原代 PBMCs 的凋亡率，并使淋巴母细胞和骨髓间充质基质细胞（BM-MSCs）中的哺乳动物雷帕霉素靶蛋白磷酸化水平恢复正常。由于目前缺乏针对 SDS 的特定治疗方法，这些结果为 ataluren 重新用于临床试验提供了依据。
