Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation

Simple Summary GATA2 deficiency is a complex disorder associated with an increased risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia. In this study, we focused on pediatric MDS patients with or without an additional GATA2 deficiency and investigated the possible mechanisms underlying disease progression. We found that disease progression was associated with an upregulation in GATA2 mRNA levels, along with the reactivation of EZH2, a gene controlled by GATA2. This was accompanied by increased histone trimethylation, a key epigenetic mark linked to EZH2 function. Additionally, we found elevated levels of the antiapoptotic protein BCL2 in patients with an advanced GATA2 deficiency, together with alterations in apoptosis-related proteins. These findings suggest the potential drivers of disease progression in pediatric GATA2 deficiency, including increased histone trimethylation and deregulated apoptosis. Therefore, this study provides a rationale for the use of the therapeutic agents venetoclax and azacitidine, offering promising options for improving patient management in the future.Abstract GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual's risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.