Abstract
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.
Highlights
Diamond Blackfan Anemia (DBA) (OMIM# 105650) is a rare (5–10/1,000,000) bone marrow (BM) failure syndrome, characterized by blockade in erythropoiesis at earlier stages (Da Costa et al, 2018) and usually affects only erythroid lineage cells in the BM, pancytopenia may be seen in rare cases (Garçon et al, 2013; Danilova and Gazda, 2015)
Only colonies of DBA-3 were taken into transcriptomic profiling due to the colony presence
Gazda et al (2006) determined that the pathways related to apoptosis and cancer had altered in adult DBA patients in remission at the time
Summary
Diamond Blackfan Anemia (DBA) (OMIM# 105650) is a rare (5–10/1,000,000) bone marrow (BM) failure syndrome, characterized by blockade in erythropoiesis at earlier stages (Da Costa et al, 2018) and usually affects only erythroid lineage cells in the BM, pancytopenia may be seen in rare cases (Garçon et al, 2013; Danilova and Gazda, 2015). DBA is usually inherited autosomal dominantly (40%), due to loss of function mutations or deletions in genes encoding ribosomal proteins. The mutations on the genes that encode ribosomal proteins are found to be linked with DBA, molecular etiology cannot be clarified in approximately 30% of the patients. Due to the mutations in genes encoding ribosomal proteins, DBA is classified as a ribosomopathy, which is a failure in ribosome biogenesis. According to the previous studies, 25% of the cases are associated with germline mutations in RPS19 ribosomal protein (Gazda et al, 2006; Garçon et al, 2013). GATA-1 and TSR2 mutations have been shown to cause DBA phenotype through X-linked inheritance pattern (Sankaran et al, 2012; Gripp et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
