ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS
ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS
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DOI：
10.1126/sciadv.adi7375
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发表时间：
2023-12-01
期刊：
影响因子：
13.6
通讯作者：
Wu，Ling-Yun
中科院分区：
文献类型：
--
作者：
Jin，Jia-Cheng;Chen，Bing-Yi;Wu，Ling-Yun
骨髓增生异常综合征（MDS）是一组起源于造血干祖细胞（HSPC）的克隆性造血肿瘤。我们之前在 MDS 患者中发现了频繁的迂回引导受体 1 (ROBO1) 突变，但 ROBO1 在造血中的确切作用仍不清楚。在这里，我们报告ROBO1缺陷会导致小鼠出现类似MDS的疾病，伴有贫血和多系发育不良，并预测MDS患者的预后不良。更具体地说，Robo1缺陷会损害HSPC稳态并破坏HSPC库，尤其是巨核细胞红系祖细胞的减少，从而导致小鼠红细胞生成的早期阶段受阻。从机制上讲，转录分析表明 Cdc42（Rho-鸟苷三磷酸酶家族的成员）充当 HSPC 中 Robo1 的下游靶基因。 Cdc42 的过度表达可部分恢复 Robo1 缺陷小鼠中 HSPC 的自我更新和红细胞生成。总的来说，我们的结果表明 ROBO1 在通过 CDC42 维持 HSPC 稳态和红细胞生成方面发挥着重要作用。
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role ofROBO1in hematopoiesis remains poorly delineated. Here, we report thatROBO1deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically,Robo1deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates thatCdc42, a member of the Rho–guanosine triphosphatase family, acts as a downstream target gene forRobo1in HSPCs. Overexpression ofCdc42partially restores the self-renewal and erythropoiesis of HSPCs inRobo1-deficient mice. Collectively, our result implicates the essential role ofROBO1in maintaining HSPC homeostasis and erythropoiesis viaCDC42.