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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_D094EC857F1A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation.
Périodique
Cancers
Auteur⸱e⸱s
Schreiber F., Piontek G., Schneider-Kimoto Y., Schwarz-Furlan S., De Vito R., Locatelli F., Gengler C., Yoshimi A., Jung A., Klauschen F., Niemeyer C.M., Erlacher M., Rudelius M.
ISSN
2072-6694 (Print)
ISSN-L
2072-6694
Statut éditorial
Publié
Date de publication
26/11/2023
Peer-reviewed
Oui
Volume
15
Numéro
23
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
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.
Mots-clé
GATA2 deficiency, apoptosis, childhood, myelodysplastic syndrome, pediatric
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/12/2023 9:08
Dernière modification de la notice
19/12/2023 7:12
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