Background and aims: MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2. The disease is characterized by progressive multilineage cytopenia, a heterogenous clinical presentation with an infectious phenotype, particularly involving infection by mycobacteria and herpesviruses, as well as malignant complications. We wanted to describe localization of variants in the GATA2, antiviral and inflammatory responses to herpesviruses and relevant microbial ligands, as well as development of malignancy in a small group of patients with GATA2 mutations.
Methods: Patients with identified GATA2 mutations and a relevant immunological and clinical presentation were included. PBMCs from patients and controls were infected with herpes simplex virus (HSV)-1, varicella zoster virus (VZV) or stimulated by relevant PAMPs. Antiviral and inflammatory innate immune responses were measured at mRNA and protein level by RT-qPCR and mesoscale technology, respectively. Moreover, T cell activation and NK cell degranulation was measured.
Results: We included seven patients with mutations located within the two DNA binding domains of GATA2. Two of four individuals with germline GATA2 mutations had severe monocytopenia, impaired antiviral responses, and one developed myelodysplastic syndrome. Three patients with AML harbored somatic GATA2 mutations but did not display any infectious phenotype. Two healthy carriers of GATA2 mutations had normal monocyte numbers and inflammatory responses.
Conclusions: This study clearly demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by different mutations in the same transcription factor. Germline mutations result in classical MonoMAC with impaired antiviral responses and incomplete penetrance, whereas somatic mutations may cause AML.