Proerythroblast cells of diamond-blackfan anemia patients with RPS19 and CECR1 mutations have similar transcriptomic signature

Diamond Blackfan Anemia (DBA) is an inherited bone marrow 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 bone marrow, we investigated the
transcriptomic profile of 3 different cell types of bone marrow resident
cells of DBA patients and compared them with healthy donors. From bone
marrow aspirates bone marrow mononuclear cells 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 bone marrow niche may have a role in DBA pathogenesis.