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Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes

Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinica...

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Autores principales: Walne, Amanda J., Vulliamy, Tom, Bewicke-Copley, Findlay, Wang, Jun, Alnajar, Jenna, Bridger, Maria G., Ma, Bernard, Tummala, Hemanth, Dokal, Inderjeet
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153011/
https://www.ncbi.nlm.nih.gov/pubmed/34625797
http://dx.doi.org/10.1182/bloodadvances.2021005360
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author Walne, Amanda J.
Vulliamy, Tom
Bewicke-Copley, Findlay
Wang, Jun
Alnajar, Jenna
Bridger, Maria G.
Ma, Bernard
Tummala, Hemanth
Dokal, Inderjeet
author_facet Walne, Amanda J.
Vulliamy, Tom
Bewicke-Copley, Findlay
Wang, Jun
Alnajar, Jenna
Bridger, Maria G.
Ma, Bernard
Tummala, Hemanth
Dokal, Inderjeet
author_sort Walne, Amanda J.
collection PubMed
description Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinically and genetically characterized as Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and dyskeratosis congenita (DC). We hypothesized that annotating whole-blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood-derived transcriptomes revealed significant skewing toward upregulated genes in patients with FA when compared with controls. Patients with SDS or DC also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense-mediated decay), and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cutoff (false discovery rate < 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterized patients with BMF revealed a striking overlap of genes, including 22 from the discovery set, which indicates a unified transcriptional drive across the classic (FA, SDS, and DC) and uncharacterized BMF subtypes. This study has relevance in disease pathogenesis, for example, in explaining the features (including the BMF) common to all patients with IBMF and suggests harnessing this transcriptional signature for patient benefit.
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spelling pubmed-91530112022-05-31 Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes Walne, Amanda J. Vulliamy, Tom Bewicke-Copley, Findlay Wang, Jun Alnajar, Jenna Bridger, Maria G. Ma, Bernard Tummala, Hemanth Dokal, Inderjeet Blood Adv Hematopoiesis and Stem Cells Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole-blood transcriptomic profiling in a subset of patients with inherited bone marrow failure (IBMF) whose diseases are clinically and genetically characterized as Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and dyskeratosis congenita (DC). We hypothesized that annotating whole-blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood-derived transcriptomes revealed significant skewing toward upregulated genes in patients with FA when compared with controls. Patients with SDS or DC also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense-mediated decay), and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cutoff (false discovery rate < 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterized patients with BMF revealed a striking overlap of genes, including 22 from the discovery set, which indicates a unified transcriptional drive across the classic (FA, SDS, and DC) and uncharacterized BMF subtypes. This study has relevance in disease pathogenesis, for example, in explaining the features (including the BMF) common to all patients with IBMF and suggests harnessing this transcriptional signature for patient benefit. American Society of Hematology 2021-12-09 /pmc/articles/PMC9153011/ /pubmed/34625797 http://dx.doi.org/10.1182/bloodadvances.2021005360 Text en © 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
spellingShingle Hematopoiesis and Stem Cells
Walne, Amanda J.
Vulliamy, Tom
Bewicke-Copley, Findlay
Wang, Jun
Alnajar, Jenna
Bridger, Maria G.
Ma, Bernard
Tummala, Hemanth
Dokal, Inderjeet
Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title_full Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title_fullStr Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title_full_unstemmed Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title_short Genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
title_sort genome-wide whole-blood transcriptome profiling across inherited bone marrow failure subtypes
topic Hematopoiesis and Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9153011/
https://www.ncbi.nlm.nih.gov/pubmed/34625797
http://dx.doi.org/10.1182/bloodadvances.2021005360
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