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

Schreiber F, Piontek G, Schneider-Kimoto Y, Schwarz-Furlan S, De Vito R, Locatelli F, Gengler C, Yoshimi A, Jung A, Klauschen F, Niemeyer CM, Erlacher M, Rudelius M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Cancers MDPI

Book Volume: 15

Journal Issue: 23

DOI: 10.3390/cancers15235594

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.

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Kliniken Ostallgäu-Kaufbeuren Anstalt des öffentlichen Rechts Buchloe - Füssen - Kaufbeuren DE Germany (DE) Ospedale Pediatrico Bambino Gesu IT Italy (IT) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) CH Switzerland (CH)

How to cite

APA:

Schreiber, F., Piontek, G., Schneider-Kimoto, Y., Schwarz-Furlan, S., De Vito, R., Locatelli, F.,... Rudelius, M. (2023). Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation. Cancers, 15(23). https://doi.org/10.3390/cancers15235594

MLA:

Schreiber, Franziska, et al. "Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation." Cancers 15.23 (2023).

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