A new in-vivo zebrafish model with cecr1b deficiency fully recapitulates the pathological features of human adenosine deaminase 2 deficiency

Deficiency of adenosine deaminase 2 (DADA2) is a rare genetic disease caused by recessive mutations in the ADA2 (CECR1) gene. Patients affected by DADA2 display immune-hematological manifestations, systemic inflammation, and recurrent strokes. Current therapies mitigate the symptoms but are not resolutive except for allogeneic hematopoietic stem cell transplantation (HSCT), which is extremely risky. Advances in therapeutical treatments are hampered by the poor knowledge of DADA2 pathogenesis due to the lack of an animal model since rodents do not have an ADA2 orthologue. Zebrafish (Danio rerio) has two ADA2 orthologues, cecr1a and cecr1b, with the latter sharing a conserved function with ADA2. We generated and characterized a cecr1b-knock down (KD) zebrafish model recapitulating the DADA2 immuno-hematological and vascular manifestations. We corrected the DADA2 phenotypes by administrating drug therapies currently used for DADA2 patients or the recombinant human ADA2 protein, further confirming Cecr1 functional conservation between the two species. By characterizing the hematological phenotype in detail, we found a very early defect in hematopoietic stem and progenitor cells (HSPCs) specification from the hemogenic endothelium (HE) during definitive hematopoiesis. This defect was accompanied by spontaneous inflammation due to enhanced expression of pro-inflammatory cytokines and polarization of M1-like pro-inflammatory macrophages. These defects were dependent on the dysregulation of the adenosine-mediated a2br/cxcl8/runx/cmyb signaling pathway. Pharmacological modulation of this pathway corrected early and late defects, opening a new therapeutical strategy for DADA2 patients. Our data provide the mechanistic link between ADA2 deficiency and hematological abnormalities/inflammation observed in patients.