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Early Bone Marrow Alterations in Patients with Adenosine Deaminase 2 Deficiency Across Disease Phenotypes and Severities
29 Pages Posted: 18 Apr 2024
More...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 hematological abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored.
Methods: We comprehensively examined the BM of 18 DADA2 patients, focusing on hematopoietic stem cells (HSCs), progenitor cells, mature cell populations, and mesenchymal stromal cells (MSCs).
Findings: 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 non-severe hematological manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematological 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 MSCs in DADA2 patients exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage.
Interpretation: Our exploration into the BM landscape of DADA2 patients sheds light on the critical hematological dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation.
Funding: Fondazione Telethon (SR-Tiget Core Grant, Tele21-A5 and Tele21-E5) to AM and RDM, the Italian Ministry of Health (Progetto Ricerca Finalizzata 2019, RF-2019-12370600) to MG, CD, AA, and AM, PNRR 2022 (PNRR-MR1-2022-12376594) to FB and AA, and the Else Kröner-Fresenius-Stiftung (EKFS) prize for Medical Research 2020 to AA.
Declaration of Interest: Authors declare no conflicts of interest.
Ethical Approval: In addition, patients enrolled at the IRCCS San Raffaele Hospital consented to the TIGET09 observational protocol for biological banking approved by the local ethical committee.
Keywords: adenosine deaminase 2 deficiency, bone marrow, bone marrow failure, cytopenia, hematopoietic stem cell transplantation, mesenchymal stroma cells, senescence
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