Downregulation of SATB1 by miRNAs reduces megakaryocyte/erythroid progenitor expansion in preclinical models of Diamond-Blackfan anemia.

Autor: Wilkes MC; Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA., Scanlon V; Yale Stem Cell Center, Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT., Shibuya A; Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA., Cepika AM; Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA., Eskin A; Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA., Chen Z; Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA., Narla A; Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA., Glader B; Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA., Roncarolo MG; Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA., Nelson SF; Department of Pathology and Laboratory Medicine¸ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA., Sakamoto KM; Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA. Electronic address: kmsakamo@stanford.edu.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2022 Jul; Vol. 111, pp. 66-78. Date of Electronic Publication: 2022 Apr 20.
DOI: 10.1016/j.exphem.2022.04.005
Abstrakt: 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 more than 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is due predominantly 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 sequencing on mRNA and miRNA from RPS19-deficient human hematopoietic stem and progenitor cells (HSPCs) and compared 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 affect expansion of committed erythroid progenitors, indicating ribosomal insufficiency affects multiple stages during erythroid differentiation.
Competing Interests: Conflict of interest disclosure The authors have no competing interests to declare.
(Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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