GATA2 tumor suppressive role revealed in ERG - AML mouse model, unveiling a preleukemic phenotype
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE143308 | GEO | 2023/09/15
REPOSITORIES: GEO
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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.
2022-07-01 | GSE143238 | GEO
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:GATA2 haploinsufficiency predisposing to lymphedema reveals key roles in lymphatic vascular development.
| PRJEB9436 | ENA
Project description:While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.
2023-02-21 | GSE224904 | GEO
Project description:While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.
2023-02-22 | GSE201968 | 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:Somatic and germline mutations in GATA2 were recently identified in patients diagnosed with monoMAC, the hallmarks of which include monocytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. GATA2 mutations are thought to result in loss of function or haploinsufficiency, but the precise mechanism for the development of cytopenias, immunodeficiency, and susceptibility to MDS remains to be elucidated. MicroRNA (miR) represents a unique mechanism of post-transcriptional gene regulation. In this study we generated microRNA profiles of patient derived monoMAC cell lines followed by functional studies to identify aberrant miRs and their targets, which could potentially cooperate with GATA2 deficiency in generating cytopenias and hematologic disease. In our study, eight miRs were significantly differentially expressed (≥ 2-fold; p ≤ 0.05) as determined by microRNA microarray profiles; miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582-5p showed increased expression in monoMAC cell lines compared to controls, while miR-223 and miR-424-3p showed significantly decreased expression. Among the differentially expressed miRs that were validated by quantitative RT-PCR was miR-181c, which demonstrated a 2.2 fold increase in expression in monoMAC cell lines (p = 0.013). Among the target transcripts potentially regulated by miR-181c, MCL1 expression was significantly decreased (2 fold; p = 0.018) in monoMAC cell lines in comparison to control cell lines. Transient transfection of miR-181c in Ly8 cells resulted in 40% decrease of MCL1 mRNA level, suggesting that miR-181c negatively regulates MCL1 in MonoMAC. These findings indicate that monoMAC/GATA2 deficiency is associated with significantly decreased expression of MCL1 possibly through negative regulation involving miR-181c. Deletion of Mcl1 is known to cause apoptosis, loss of HSCs, and cytopenias in murine studies. Thus, down-regulation of MCL1 seen in monoMAC/GATA2 deficiency may similarly favor unregulated apoptosis and the depletion of hematopoietic progenitors resulting in cytopenias, immunodeficiency, and risk of MDS/AML.
2023-06-23 | GSE51132 | GEO
Project description:Although certain human genetic variants are conspicuously loss-of-function, decoding the impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2-deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling promotes bone marrow failure, GATA2-deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.
2023-02-27 | GSE199464 | GEO
Project description:GATA2 tumor suppressive role revealed in ERG - AML mouse model, unveiling a preleukemic phenotype
| PRJNA599960 | ENA