Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature

Frontiers in Physiology

Duygu Uckan Cetinkaya¹  Gunes Esendagli²  M. Alper Kursunel²  Ekim Z. Taskiran³  Beren Karaosmanoglu⁴  Fatma Gumruk⁶  Sule Unal⁶ 

[1] Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey;Department of Basic Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey;Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara, Turkey;Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey;Division of Pediatric Hematology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey;Research Center for Fanconi Anemia and Other IBMFS, Hacettepe University, Ankara, Turkey;

关键词: Diamond Blackfan Anemia;    ribosomopathy;    proerythroblast;    RPS19;    CECR1;    transcriptomics;   

DOI  :  10.3389/fphys.2021.679919

来源: DOAJ

【 摘 要 】

Diamond Blackfan Anemia (DBA) is an inherited bone marrow (BM) failure syndrome, characterized by a paucity of erythroid differentiation. DBA is mainly caused by the mutations in ribosomal protein genes, hence classified as ribosomopathy. However, in approximately 30% of patients, the molecular etiology cannot be discovered. RPS19 germline mutations caused 25% of the cases. On the other hand, CECR1 mutations also cause phenotypes similar to DBA but not being a ribosomopathy. Due to the blockade of erythropoiesis in the BM, we investigated the transcriptomic profile of three different cell types of BM resident cells of DBA patients and compared them with healthy donors. From BM aspirates BM mononuclear cells (MNCs) were isolated and hematopoietic stem cells (HSC) [CD71–CD34+ CD38mo/lo], megakaryocyte–erythroid progenitor cells (MEP) [CD71–CD34+ CD38hi] and Proerythroblasts [CD71+ CD117+ CD38+] were sorted and analyzed with a transcriptomic approach. Among all these cells, proerythroblasts had the most different transcriptomic profile. The genes associated with cellular stress/immune responses were increased and some of the transcription factors that play a role in erythroid differentiation had altered expression in DBA proerythroblasts. We also showed that gene expression levels of ribosomal proteins were decreased in DBA proerythroblasts. In addition to these, colony formation assay (CFU-E) provided functional evidence of the failure of erythroid differentiation in DBA patients. According to our findings that all patients resembling both RPS19 and CECR1 mutations have common transcriptomic signatures, it may be possible that inflammatory BM niche may have a role in DBA pathogenesis.

【 授权许可】

Unknown