ADA2 Orchestrates Interferon Responses and Safeguards Hematopoietic Stem Cell Integrity

Dimitri Bulté – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute; Alessandro Romano – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute; Andrea Ottorini – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute; Federica Barzaghi – Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute; Emanuela Pettinato – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute; Alessandro Aiuti – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute; Alessandra Mortellaro – San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute

Abstract Text: Adenosine deaminase 2 (ADA2) is an extracellular enzyme that catalyzes the conversion of adenosine to inosine. It is primarily expressed and secreted by myeloid cells, particularly monocytes and macrophages, and plays a critical role in modulating inflammatory immune responses. Loss-of-function mutations in the ADA2 gene cause Deficiency of Adenosine Deaminase 2 (DADA2), a systemic autoinflammatory disorder characterized by vasculitis, immunodeficiency, and bone marrow (BM) failure. A hallmark of DADA2 is a pronounced type I interferon (IFN) signature, which contributes to disease pathogenesis; however, the precise role of ADA2 in IFN signaling and hematopoietic dysfunction remains unclear.
We identified the cGAS–STING and JAK–STAT pathways as key mediators of the exaggerated IFN response in DADA2, supporting the rationale for targeted pharmacological inhibition. Furthermore, restoration of ADA2 function through gene therapy normalized IFN signaling, highlighting its potential as a long-term curative approach. In DADA2 patients, hematopoietic stem and progenitor cells (HSPCs) display reduced frequency and clonogenic potential, even in the absence of overt hematological symptoms. Single-cell RNA sequencing revealed widespread transcriptional alterations across all HSPC subtypes. Additional studies showed that DADA2 mesenchymal stromal cells are functionally impaired and contribute to hematopoietic defects, pointing to both cell-intrinsic and niche-driven mechanisms of bone marrow failure.
Together, these findings define ADA2 as a critical regulator of inflammatory balance and hematopoietic homeostasis, advancing our understanding of DADA2 pathogenesis and uncovering broader principles of bone marrow failure.