Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is associated with anemia, congenital anomalies, and cancer predisposition. It is categorized as a ribosomopathy, because over 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is predominantly due to a block and delay in early committed erythropoiesis with reduced Megakaryocyte/Erythroid Progenitors (MEPs). To understand the molecular pathways leading to pathogenesis of DBA, we performed RNA-seq on mRNA and miRNA from RPS19-deficient human hematopoietic stem and progenitor cells (HSPCs) and compared an existing database documenting transcript fluctuations across stages of early normal erythropoiesis. We determined the chromatin regulator, SATB1 was prematurely downregulated through the coordinated action of upregulated miR-34 and miR-30 during differentiation in ribosomal-insufficiency. Restoration of SATB1 rescued MEP expansion, leading to a modest improvement in erythroid and megakaryocyte expansion in RPS19-insufficiency. However, SATB1 expression did not impact expansion of committed erythroid progenitors, indicating ribosomal insufficiency impacts multiple stages during erythroid differentiation.
Copyright © 2022. Published by Elsevier Inc.

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