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<p>Diamond-Blackfan Anaemia (DBA) is a rare inherited bone marrow failure syndrome conventionally attributed to ribosomal protein gene haploinsufficiency, resulting in impaired ribosome assembly and compromised erythroid precursor viability. However, contemporary research reveals considerably more complex molecular mechanisms driving disease pathology. This study aimed to comprehensively characterise the transcriptional and post-transcriptional regulatory networks contributing to DBA pathogenesis using integrative mRNA–miRNA sequencing of patient-derived bone marrow specimens. Our analysis revealed extensive dysregulation across immune, proliferative, and erythroid differentiation pathways. A coordinated elevation of immune-associated genes, such as TNF, CXCL8, TLR2/4, and CD44, suggests the establishment of a hyperinflammatory bone marrow microenvironment. In contrast, significant downregulation of essential mitotic and epigenetic regulatory factors, particularly CDC25A/C, CDK1/2, and AURKA, reflects disrupted cell cycle dynamics and impaired hematopoietic proliferation. Integrative miRNA–mRNA analysis identified dysregulated miRNAs as critical mediators of these processes. Downregulation of anti-inflammatory miRNAs (e.g., miR-93-5p, miR-143-3p, miR-19a-3p) and upregulation of mitotic suppressor miRNAs (e.g., let-7a, miR-141, miR-31, miR-21) indicate post-transcriptional disruption of immune and cell-cycle balance. Together, these findings reveal a multifaceted regulatory framework in DBA where transcriptional and miRNA-mediated perturbations converge to drive immune activation and impaired erythropoiesis, challenging prevailing ribosomopathy-centric models and highlighting potential molecular targets for therapeutic intervention.</p> Graphical abstract <p>Integrated miRNA–mRNA regulatory landscape in Diamond-Blackfan Anaemia (DBA). The graphical abstract illustrates the coordinated miRNA-mRNA dysregulation in DBA bone marrow, highlighting key differentially expressed miRNAs and their target hub genes. Downregulated miRNAs (Red) lead to the de-repression of pro-inflammatory/apoptotic genes, promoting a hyper-inflammatory bone marrow microenvironment. In parallel, upregulated miRNAs (Green) suppress critical cell cycle regulators, contributing to mitotic arrest. The combined effect of these regulatory imbalances, alongside the downregulation of erythroid-promoting factors such as GATA1 and lineage-supportive miRNAs, suggests a disrupted erythropoietic maturation. Collectively, these findings support a model wherein coordinated post-transcriptional dysregulation contributes to impaired erythroid proliferation and differentiation in DBA, offering mechanistic insights and putative targets for therapeutic intervention. (Created in BioRender)</p>

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Comprehensive transcriptomic analysis highlights immune and cell-cycle dysregulation in Diamond-Blackfan Anaemia

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Isha Goel,
  • Ashikh Seethy,
  • Karthikeyan Pethusamy,
  • Deepak Kumar,
  • Ruby Dhar,
  • Tulika Seth,
  • Subhradip Karmakar

摘要

Diamond-Blackfan Anaemia (DBA) is a rare inherited bone marrow failure syndrome conventionally attributed to ribosomal protein gene haploinsufficiency, resulting in impaired ribosome assembly and compromised erythroid precursor viability. However, contemporary research reveals considerably more complex molecular mechanisms driving disease pathology. This study aimed to comprehensively characterise the transcriptional and post-transcriptional regulatory networks contributing to DBA pathogenesis using integrative mRNA–miRNA sequencing of patient-derived bone marrow specimens. Our analysis revealed extensive dysregulation across immune, proliferative, and erythroid differentiation pathways. A coordinated elevation of immune-associated genes, such as TNF, CXCL8, TLR2/4, and CD44, suggests the establishment of a hyperinflammatory bone marrow microenvironment. In contrast, significant downregulation of essential mitotic and epigenetic regulatory factors, particularly CDC25A/C, CDK1/2, and AURKA, reflects disrupted cell cycle dynamics and impaired hematopoietic proliferation. Integrative miRNA–mRNA analysis identified dysregulated miRNAs as critical mediators of these processes. Downregulation of anti-inflammatory miRNAs (e.g., miR-93-5p, miR-143-3p, miR-19a-3p) and upregulation of mitotic suppressor miRNAs (e.g., let-7a, miR-141, miR-31, miR-21) indicate post-transcriptional disruption of immune and cell-cycle balance. Together, these findings reveal a multifaceted regulatory framework in DBA where transcriptional and miRNA-mediated perturbations converge to drive immune activation and impaired erythropoiesis, challenging prevailing ribosomopathy-centric models and highlighting potential molecular targets for therapeutic intervention.

Graphical abstract

Integrated miRNA–mRNA regulatory landscape in Diamond-Blackfan Anaemia (DBA). The graphical abstract illustrates the coordinated miRNA-mRNA dysregulation in DBA bone marrow, highlighting key differentially expressed miRNAs and their target hub genes. Downregulated miRNAs (Red) lead to the de-repression of pro-inflammatory/apoptotic genes, promoting a hyper-inflammatory bone marrow microenvironment. In parallel, upregulated miRNAs (Green) suppress critical cell cycle regulators, contributing to mitotic arrest. The combined effect of these regulatory imbalances, alongside the downregulation of erythroid-promoting factors such as GATA1 and lineage-supportive miRNAs, suggests a disrupted erythropoietic maturation. Collectively, these findings support a model wherein coordinated post-transcriptional dysregulation contributes to impaired erythroid proliferation and differentiation in DBA, offering mechanistic insights and putative targets for therapeutic intervention. (Created in BioRender)