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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 (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 etio...

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Autores principales: Karaosmanoglu, Beren, Kursunel, M. Alper, Uckan Cetinkaya, Duygu, Gumruk, Fatma, Esendagli, Gunes, Unal, Sule, Taskiran, Ekim Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226250/
https://www.ncbi.nlm.nih.gov/pubmed/34177624
http://dx.doi.org/10.3389/fphys.2021.679919
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author Karaosmanoglu, Beren
Kursunel, M. Alper
Uckan Cetinkaya, Duygu
Gumruk, Fatma
Esendagli, Gunes
Unal, Sule
Taskiran, Ekim Z.
author_facet Karaosmanoglu, Beren
Kursunel, M. Alper
Uckan Cetinkaya, Duygu
Gumruk, Fatma
Esendagli, Gunes
Unal, Sule
Taskiran, Ekim Z.
author_sort Karaosmanoglu, Beren
collection PubMed
description 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(+) CD38(mo/lo)], megakaryocyte–erythroid progenitor cells (MEP) [CD71(–)CD34(+) CD38(hi)] 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.
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spelling pubmed-82262502021-06-26 Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature Karaosmanoglu, Beren Kursunel, M. Alper Uckan Cetinkaya, Duygu Gumruk, Fatma Esendagli, Gunes Unal, Sule Taskiran, Ekim Z. Front Physiol Physiology 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(+) CD38(mo/lo)], megakaryocyte–erythroid progenitor cells (MEP) [CD71(–)CD34(+) CD38(hi)] 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. Frontiers Media S.A. 2021-06-11 /pmc/articles/PMC8226250/ /pubmed/34177624 http://dx.doi.org/10.3389/fphys.2021.679919 Text en Copyright © 2021 Karaosmanoglu, Kursunel, Uckan Cetinkaya, Gumruk, Esendagli, Unal and Taskiran. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Karaosmanoglu, Beren
Kursunel, M. Alper
Uckan Cetinkaya, Duygu
Gumruk, Fatma
Esendagli, Gunes
Unal, Sule
Taskiran, Ekim Z.
Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title_full Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title_fullStr Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title_full_unstemmed Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title_short Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature
title_sort proerythroblast cells of diamond-blackfan anemia patients with rps19 and cecr1 mutations have similar transcriptomic signature
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226250/
https://www.ncbi.nlm.nih.gov/pubmed/34177624
http://dx.doi.org/10.3389/fphys.2021.679919
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