Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities.
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Bulté Dimitri, Barzaghi Federica, Mesa-Nuñez Cristina, Rigamonti Chiara, Basso-Ricci Luca, Visconti Camilla, Crippa Stefania, Pettinato Emanuela, Gilioli Diego, Milani Raffaella, Quaranta Pamela, Caorsi Roberta, Cafaro Alessia, Cangemi Giuliana, Lupia Michela, Schena Francesca, Grossi Alice, Di Colo Giulia, Federici Silvia, Insalaco Antonella, De Benedetti Fabrizio, Marktel Sarah, Di Micco Raffaella, Bernardo Maria Ester, Scala Serena, Cicalese Maria Pia, Conti Francesca, Miano Maurizio, Gattorno Marco, Dufour Carlo, Aiuti Alessandro, Mortellaro Alessandra
Аннотация
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.