GATA2 tumor suppressive role is displayed in an ERG driven AML mouse, unveiling a preleukemic phenotype
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ABSTRACT:
PROVIDER: PRJNA599376 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10843306.fastq.gz | Fastqsanger.gz | |||
| SRR10843307.fastq.gz | Fastqsanger.gz | |||
| SRR10843308.fastq.gz | Fastqsanger.gz | |||
| SRR10843309.fastq.gz | Fastqsanger.gz | |||
| SRR10843310.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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Project description:GATA2 tumor suppressive role revealed in ERG - AML mouse model, unveiling a preleukemic phenotype
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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.
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Project description:We generated homozygous GATA2 knockout human embryonic stem cells (GATA2-/- hESCs) and analyzed their blood differentiation potential. Paritcularly at the hemogenic endothelium (HE) stage and hematopoietic progenitor cell (HPC) stage. Our result revealed that GATA2-/- hESCs displayed attenuated generation of CD34+CD43+ HPCs, due to the impairment of endothelial to hematopoietic transition (EHT). However, GATA2-/- hESCs retained the potential to generate erythroblasts, macrophages, but never granulocytes. Through RNA-Seq and further rescue experiment, we further identified that SPI1 was responsible for the defect of GATA2-/- hESCs in generation of CD34+CD43+ HPCs and granulocytes.
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Project description:Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. The cell type transitions within this process are tightly controlled, and loss of control can lead to inappropriate proliferation and leukemic transformation. We and others have previously described seven transcriptional regulators (heptad; LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) which bind key haematopoietic genes in normal human CD34+ haematopoietic stem and progenitor cells (HSPCs). Heptad factors form a densely interconnected circuit by binding combinatorically at their own, and each other’s, regulatory elements. However, the precise role of the heptad throughout normal and leukemic haematopoiesis, including whether all seven factors act together in single cells, and whether heptad perturbation can influence cell fate decisions remain unclear. In this study we integrate bulk and single cell data in normal human HSPCs and leukemic cells and find that chromatin conformation at key heptad regulatory elements is predictive of cell identity in normal and leukemic progenitors. The interconnected heptad circuit identified in normal HSPCs persists in AML, but single cell transcriptomics suggest that specific heptad sub-circuits exist in individual cells, and we show that GATA2, TAL1 and ERG play key roles in regulating the stem to erythroid transition in both normal and leukemic contexts.
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2021-05-27 | GSE158796 | GEO
Project description:Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. The cell type transitions within this process are tightly controlled, and loss of control can lead to inappropriate proliferation and leukemic transformation. We and others have previously described seven transcriptional regulators (heptad; LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) which bind key haematopoietic genes in normal human CD34+ haematopoietic stem and progenitor cells (HSPCs). Heptad factors form a densely interconnected circuit by binding combinatorically at their own, and each other’s, regulatory elements. However, the precise role of the heptad throughout normal and leukemic haematopoiesis, including whether all seven factors act together in single cells, and whether heptad perturbation can influence cell fate decisions remain unclear. In this study we integrate bulk and single cell data in normal human HSPCs and leukemic cells and find that chromatin conformation at key heptad regulatory elements is predictive of cell identity in normal and leukemic progenitors. The interconnected heptad circuit identified in normal HSPCs persists in AML, but single cell transcriptomics suggest that specific heptad sub-circuits exist in individual cells, and we show that GATA2, TAL1 and ERG play key roles in regulating the stem to erythroid transition in both normal and leukemic contexts.
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Project description:Fusion proteins involving the ETS factor ERG have been associated with multiple cancers such as Ewing's sarcoma and prostate cancer. In acute myeloid leukemias harboring t(16;21) another ERG fusion protein is expressed, FUS-ERG. Here, we found that this FUS-ERG oncofusion protein acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LNMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR-RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-Trans Retinoic Acid treatment of t(16;21) cells as well as FUS-ERG knock down alleviate the myeloid differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.
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