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GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2- mutated MDS/AML

ABSTRACT: GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2- mutated MDS/AML

PROVIDER: PRJNA413065 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6129270_1.fastq.gz	Fastqsanger.gz
	SRR6129270_2.fastq.gz	Fastqsanger.gz
	SRR6129271_1.fastq.gz	Fastqsanger.gz
	SRR6129271_2.fastq.gz	Fastqsanger.gz
	SRR6129272_1.fastq.gz	Fastqsanger.gz

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Project description:The transcription factor (TF) GATA2, is crucial for the formation, and lifelong homeostasis of hematopoietic stem cells. Mono-Allelic germline disruptions of GATA2, result in haploinsufficiency syndromes. These disorders display variable manifestations, including immune deficiency, lymphedema, pulmonary proteinosis, and bone marrow failure. The later is presented by myelodysplastic changes (MDS), that subsequently evolve to leukemia (AML). MDS/AML are the most devastating, yet most consistent outcomes, designating GATA2 deficiency as one major predisposing condition to AML development. To date, biomolecular trajectories of GATA2 deficiency, just vaguely delineated explanatory mechanisms. Experimental models recapitulating the disease evolution are meager, and functional studies are thus hampered. Here, we created murine models, reflecting the evolution of GATA2 deficiency, from gestational stage, to malignancy. We imposed the oncogenic driving force of TF ERG, upon Gata2 heterozygote and WT mice, to create a credible model. Both ERG/Gata2WT, and ERG/Gata2het mice developed leukemia, yet ERG/Gata2het, sustained an accelerated disease, resulting in diminished survival (p<0.0001). Subsequently, we obtained expression profiles of pre-leukemic blood precursors, using high throughput genomics, followed by functional assessments of self-renewal and cycling capacities. These studies elucidated a unique proliferative phenotype held by ERG/Gata2het progenitors. Additional expression analyses, metabolic assays, and electrons-microscopy inspections, suggested ERG/Gata2het progenitors uniquely relay on oxidative phosphorylation, and harbor alterations in mitochondrial structure and function. Excitingly, similar expression signature and morphological features were observed in human GATA2+/R396W cells, and in profiles of Inv(3)/GATA2MUT AML’s. We here provide new insights into GATA2 deficiency evolutionary course, underscoring the need to deconvolute pre-malignant stages in translational studies.

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GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2- mutated MDS/AML

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