Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities - 12/10/24

Doi : 10.1016/j.jaci.2024.09.007

Dimitri Bulté, PhD ^a,^{^{∗
These authors contributed equally to this work and share first authorship.}}, Federica Barzaghi, MD, PhD ^b,^{^{∗
These authors contributed equally to this work and share first authorship.}}, Cristina Mesa-Nuñez, PhD ^a, Chiara Rigamonti, MSc ^a,^c, Luca Basso-Ricci, MSc ^a, Camilla Visconti, MD ^b, Stefania Crippa, PhD ^a, Emanuela Pettinato, MSc ^a, Diego Gilioli, PhD ^a, Raffaella Milani, MD ^d, Pamela Quaranta, PhD ^a, Roberta Caorsi, MD ^e, Alessia Cafaro, Pharm ^f, Giuliana Cangemi, PhD ^f, Michela Lupia, PhD ^g, Francesca Schena, PhD ^e, Alice Grossi, PhD ^h, Giulia Di Colo, MD ^c,ⁱ, Silvia Federici, MD, PhD ^j, Antonella Insalaco, MD ^j, Fabrizio De Benedetti, MD, PhD ^j, Sarah Marktel, MD ^k, Raffaella Di Micco, PhD ^a, Maria Ester Bernardo, MD, PhD ^a,^b,^c, Serena Scala, PhD ^a, Maria Pia Cicalese, MD, PhD ^a,^b,^c, Francesca Conti, MD ^l,^m, Maurizio Miano, MD ^g, Marco Gattorno, MD ^e, Carlo Dufour, MD ^g, Alessandro Aiuti, MD, PhD ^a,^b,^c, Alessandra Mortellaro, PhD ^a,^⁎
^a San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
^b Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
^c Vita-Salute San Raffaele University, Milan, Italy
^d Immunohematology and Transfusion Medicine Unit, IRCCS Ospedale San Raffaele, Milan, Italy
^e UOC Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^f Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^g Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^h Laboratorio Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italy
ⁱ Immunology, Rheumatology, Allergy and Rare Disease Unit, IRCCS San Raffaele Hospital, Milan, Italy
^j Division of Rheumatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
^k Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
^l Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
^m Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

^∗Corresponding author: Alessandra Mortellaro, PhD, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)IRCCS San Raffaele Scientific InstituteVia Olgettina 60Milan20132Italy

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 12 October 2024

Graphical abstract

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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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Key words : Adenosine deaminase 2 deficiency, bone marrow, bone marrow failure, cytopenia, hematopoietic stem cell transplantation, mesenchymal stromal cells, senescence

Abbreviations used : BFU, BM, BMF, CFU, DADA2, DAPI, HD, HSCT, HSPC, MSC, PB, TEMRA, T-LGL