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Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities. | LitMetric

AI Article Synopsis

  • DADA2 is a rare genetic disease caused by mutations in the ADA2 gene, leading to a range of symptoms such as vasculitis and immune deficiencies, but its effects on bone marrow are not well understood.
  • This study focused on analyzing bone marrow and blood from 18 DADA2 patients, revealing significant reductions in hematopoietic stem cells and other blood cell types, indicating early disruption in the bone marrow even before severe symptoms appear.
  • The findings highlight the importance of monitoring bone marrow health in DADA2 patients, as damage to stem cells and mesenchymal stromal cells can lead to further complications.

Article Abstract

Background: Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematologic abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored.

Objective: This study comprehensively examined the BM and peripheral blood of pediatric and adult patients with DADA2 presenting with rheumatologic/immunologic symptoms or severe hematologic manifestations.

Methods: Immunophenotyping of hematopoietic stem cells (HSCs), progenitor cells, and mature cell populations was performed for 18 patients with DADA2. We also conducted a characterization of mesenchymal stromal cells.

Results: Our study revealed a significant decrease in primitive HSCs and progenitor cells, alongside their reduced clonogenic capacity and multilineage differentiation potential. These BM defects were evident in patients with both severe and nonsevere hematologic manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematologic symptoms. Beyond stem cells, there was a reduction in mature cell populations in the BM and peripheral blood, affecting myeloid, erythroid, and lymphoid populations. Furthermore, BM mesenchymal stromal cells in patients with DADA2 exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage.

Conclusions: Our exploration into the BM landscape of patients with DADA2 sheds light on the critical hematologic dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation.

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Source
http://dx.doi.org/10.1016/j.jaci.2024.09.007DOI Listing

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