期刊
BLOOD ADVANCES
卷 7, 期 17, 页码 4848-4868出版社
ELSEVIER
DOI: 10.1182/bloodadvances.2023010382
关键词
-
类别
The anemias of myelodysplastic syndrome (MDS) and Diamond Blackfan anemia (DBA) are macrocytic and result from diverse genetic mutations. The fate of single erythroid marrow cells from individuals with DBA or MDS-5q was studied to understand shared mechanisms that lead to cell death. It was found that cell death occurs much later after cells upregulate transferrin receptor and initiate heme synthesis. Cells destined to die express high levels of heme-responsive genes, while surviving cells downregulate heme synthesis and upregulate DNA damage response, hypoxia, and HIF1 pathways.
The anemias of myelodysplastic syndrome (MDS) and Diamond Blackfan anemia (DBA) are generally macrocytic and always reflect ineffective erythropoiesis yet result from diverse genetic mutations. To delineate shared mechanisms that lead to cell death, we studied the fate of single erythroid marrow cells from individuals with DBA or MDS-5q. We defined an unhealthy (vs healthy) differentiation trajectory using transcriptional pseudotime and cell surface proteins. The pseudotime trajectories diverge immediately after cells upregulate transferrin receptor (CD71), import iron, and initiate heme synthesis, although cell death occurs much later. Cells destined to die express high levels of heme-responsive genes, including ribosomal protein and globin genes, whereas surviving cells downregulate heme synthesis and upregulate DNA damage response, hypoxia, and HIF1 pathways. Surprisingly, 24% +/- 12% of cells from control subjects follow the unhealthy trajectory, implying that heme might serve as a rheostat directing cells to live or die. When heme synthesis was inhibited with succinylacetone, more DBA cells followed the healthy trajectory and survived. We also noted high numbers of messages with retained introns that increased as erythroid cells matured, confirmed the rapid cycling of colony forming unit-erythroid, and demonstrated that cell cycle timing is an invariant property of differentiation stage. Including unspliced RNA in pseudotime determinations allowed us to reliably align independent data sets and accurately query stagespecific transcriptomic changes. MDS-5q (unlike DBA) results from somatic mutation, so many normal (unmutated) erythroid cells persist. By independently tracking erythroid differentiation of cells with and without chromosome 5q deletions, we gained insight into why 5q+ cells cannot expand to prevent anemia.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据