GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2- mutated MDS/AML
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PROVIDER: PRJNA413065 | ENA |
REPOSITORIES: ENA
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Project description:Although familial myelodysplasia and acute myeloid leukemia (MDS/AML) is rare, its true prevalence is likely underestimated due to wide variations in the age of onset, disease latency and outcome between and within families, with some mutation carriers remaining asymptomatic into late adulthood. Reduced penetrance is a notable feature of germline GATA2 p.Thr354Met pedigrees. In this study, we demonstrate that silencing of the wildtype (WT) GATA2 allele discriminates between symptomatic and asymptomatic carriers and is linked with allele-specific differences in DNA methylation and H3K4me3 promotor deposition, providing a molecular explanation for the clinical heterogeneity observed within a GATA2-mutated AML family.
2018-09-21 | GSE104570 | GEO
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.
2023-09-15 | GSE143308 | GEO
Project description:GATA2 mutants were discovered in families predisposed to MDS/AML and in sporadic cases of CML-blast crisis. Promyelocytic HL-60 cells were transduced with lentiviral vectors that express GATA2 WT or T354M, 355delT or L359V mutants upon addition of 4-hydroxy tamoxifen (4HT). Microarrays were performed to identify GATA2 WT signatures and differences caused by these mutations. HL-60 cells transduced with GATA2 (WT, T354M, 355delT and L359V) lentiviruses were treated with 4HT for 24 hours and RNA isolated and gene expression measured on Affymetrix microarrays.
2011-08-19 | E-GEOD-29276 | biostudies-arrayexpress
Project description:GATA2 mutants were discovered in families predisposed to MDS/AML and in sporadic cases of CML-blast crisis. Promyelocytic HL-60 cells were transduced with lentiviral vectors that express GATA2 WT or T354M, 355delT or L359V mutants upon addition of 4-hydroxy tamoxifen (4HT). Microarrays were performed to identify GATA2 WT signatures and differences caused by these mutations.
2011-08-20 | GSE29276 | GEO
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.
2022-07-01 | GSE143238 | GEO
Project description:Random monoallelic expression is defined by the allele-specific expression of genes, and by the fact that for an individual cell this monoallelic expression is neither obligate nor necessarily coordinated with the allelic expression in other cells. In order to find novel examples of random monoallelic expression in mouse, we did a transcriptome-wide survey of allele-specific gene expression in two different immortalized cell types. Lymphoblast cell lines and fibroblast cell lines were established (both clonal and nonclonal) and were used as a source of both nuclear RNA and genomic DNA. These samples were assessed for allele-specific gene expression using a custom-designed Mouse SNP Chip. A large number of genes (over 10% of those that were assessed in lymphoblast clones) displayed random monoallelic expression. For each cell line, two replicate samples of ds-cDNA were assessed for monoallelic expression, while genomic DNA was assessed as a control for possible LOH events. Nonclonal samples were used as controls for cis-acting allelic bias.
2012-02-10 | E-GEOD-35678 | biostudies-arrayexpress
Project description:Background and Purpose: Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutation has a broad spectrum of clinical phenotypes including systemic infections, lymphedema, cytopenias, MDS and AML. A comprehensive profiling of transcriptome of hematopoiesis in GATA2 deficiency is currently lacking. Methods: We performed single-cell RNA sequencing of sorted bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) from eight GATA2 deficiency patients, who had various well characterized GATA2 mutations and clinically manifest myelodysplasia. We characterized transcriptomes in lineages, computationally defined cells with chromosomal abnormalities, and described gene expression of these cells. Results: Mapping patients’ cells onto normal hematopoiesis, we observed preferred deficiency in lymphoid and myeloid progenitors, which also was evidenced in loss of heterogeneity in gene correlations. HSPCs in patients exhibited distinct gene expression pattern and gene coexpression pattern compared with its counterparts in healthy donors. Distinct lineages show different transcriptional profiles resulting from GATA2 mutations. HSCs in patients exhibited dysregulated genes in apoptosis, cell cycle and quiescence, and had increased expression of erythroid/megakaryocytic priming programs and decreased lymphoid priming programs. Thus, the prominent deficiency in myeloid/lymphoid lineages in GATA2 deficiency was partly due to expression of aberrant gene programs in HSCs prior to lineage commitment. We computationally defined cells with chromosomal abnormalities and described gene expression of these cells. DNA repair genes were downregulated in trisomy 8 cells, possibly rendering these cells vulnerable to second-hit somatic mutations and additional chromosomal abnormalities. Cells with complex cytogenetics had defects in multi-lineage differentiation and cell cycle. Conclusion: Germline GATA2 mutations modulate gene expression and change gene coexpression patterns. Distinct lineages show different transcriptional profiles resulting from GATA2 mutations. The prominent deficiency in myeloid/lymphoid lineages in GATA2 deficiency was partly due to expression of aberrant gene programs in HSCs prior to lineage commitment.
2020-06-06 | GSE135194 | GEO
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.
2017-02-09 | GSE69797 | GEO