GATA2 Deficiency and the MonoMAC Syndrome
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PROVIDER: PRJNA955848 | ENA |
REPOSITORIES: ENA
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Project description:GATA2 Deficiency and the MonoMAC Syndrome
| PRJNA955837 | ENA
Project description:Inherited or sporadic mutations in the transcription factor GATA2 have been shown to be responsible for MonoMAC syndrome, a GATA2 deficiency disease characterized by a constellation of findings including disseminated non-tuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B-lymphocytes, and myelodysplastic syndrome. Mutations in the GATA2 gene are found in ~90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain or truncation mutations elsewhere in the coding sequence. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency. Here we present a large multigeneration kindred with the clinical features of GATA2 deficiency but lacking an apparent GATA2 mutation. Whole Genome Sequencing revealed a unique Adenine-to-Thymine variant in the GATA2 -110 enhancer 116,855bp upstream of the GATA2 gene. The mutation creates a new E-box consensus in position with an existing GATA-box to generate a new hematopoietic regulatory composite element. The mutation segregates with the disease pattern in five generations of the family pedigree. Cell-type specific allelic imbalance of GATA2 expression is observed in a patient’s bone marrow with higher expression from the mutant-linked allele. Allele-specific overexpression of GATA2 is observed in CRISPR/Cas9-modified HL60 cultured cells and in luciferase assays with the enhancer mutation. This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream regulatory enhancer element in patients with MonoMAC syndrome.
2023-10-31 | GSE227436 | GEO
Project description:The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and lymphoblastic leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS.
2025-03-19 | GSE288116 | GEO
Project description:The majority (72%) of adolescents with myelodysplastic syndrome and monosomy 7 carry an underlying GATA2 deficiency. Nowadays, chemotherapy and allogenic hematopoietic stem cell transplantation (HSCT) are the only cure, pointing out the urgent need to develop reliable predictive tools. Familial cases carrying the same mutation in the GATA2 gene develop the disease at different age. The trigger of the disease is still unknown. Therefore, it is needed to understand the genetic mechanisms (mutations) and epigenetic mechanism, such as, DNA methylation, a cellular mechanism to control gene expression. Abnormal DNA methylation has been linked to several adverse outcomes, including human diseases. In this study, we deeply characterized 20 Spanish GATA2 deficient patients; study the presence of secondary mutations, clinical phenotype and DNA methylation. We have found that the most frequent secondary mutations are in STAG2 and ASXL1 genes, detected in 30% and 20% of the patients, respectively, a similar ratio has been described in a bigger cohort, showing that our 20-patient cohort is representative of the GATA2 deficiency scenario. For the first time, we found a specific hypermethylated signature in GATA2 patients, opening a novel point of view in the GATA2-patient diagnostic and facilitating the risk estimation of themselves. Furthermore, whether the methylation profiling is accurate enough, it will be useful to predict the onset of the disease progression.
2023-06-30 | E-MTAB-12551 | biostudies-arrayexpress
Project description:GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation in adolescents, present in up to 7% of pediatric myelodysplastic syndrome (MDS) and 15% of advanced MDS cases. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we generated a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2R396Q/+. While mutant mice exhibit mild defects in peripheral blood output throughout life, they display significant hematopoietic abnormalities in the bone marrow (BM), including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of BM hematopoietic progenitors revealed a loss of HSC stemness, myeloid-bias, and accelerated ageing phenotype. Importantly, we show that Gata2R396Q/+ exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced pool of HSCs and aged phenotype could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.
2024-12-23 | GSE275213 | GEO
Project description:To determine the difference of GATA2 related gene expression in blood cells. Gene expression of GATA2 deficiency comparing to a healthy person.
2022-05-17 | GSE131372 | GEO
Project description:Patients with GATA2 deficiency are predisposed to developing myelodysplastic syndrome (MDS), which can progress to acute myeloid leukemia (AML). This progression is often associated with the acquisition of additional cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are recurrently observed in GATA2 patients, but their precise roles in disease progression remain poorly understood. Here we developed a hiPSC-based system to investigate the functional impact of SETBP1 and ASXL1 mutations in the context of germline GATA2 haploinsufficiency. Using precise genome editing, we recreated patient-relevant combinations of these mutations to model distinct premalignant stages of GATA2 deficiency. We demonstrate that heterozygous GATA2 mutation alone has a limited impact on early hematopoietic progenitors, without disrupting myeloid differentiation. In contrast, acquisition of SETBP1 or ASXL1 mutations impairs hematopoietic differentiation in a GATA2 deficient background, leading to a premalignant state marked by reduced myeloid progenitor output. Strikingly, the combination of all three mutations results in a severe depletion of myeloid progenitors, closely recapitulating hematopoietic defects observed in GATA2-related MDS and highlighting a synergistic interplay among the mutations. We provide new insights into the molecular mechanism underlying GATA2 deficiency progression, revealing that SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes a novel humanized model system for studying GATA2 deficiency. This model provides new insights into the cellular and molecular events underlying the progression of myeloid impairment in GATA2 deficiency and represents a platform for testing future therapeutic strategies.
2025-10-02 | GSE265824 | GEO
Project description:GATA2 deficient patients are prone to develop myelodysplastic syndrome (MDS) that can evolve to acute myeloid leukemia (AML). The MDS progression is usually associated with the acquisition of cytogenetic and/or additional somatic alterations. Mutations in SETBP1 and ASXL1 genes are frequently observed in pediatric GATA2 patients, although how they contribute to the disease progression remains poorly understood. Here we develop a human induced pluripotent stem cells (hiPSCs)-based model to study the impact of germline GATA2 mutation along with selected somatic mutations on GATA2 deficiency progression. We found that, while germline heterozygous GATA2 mutation alone is insufficient to induce an impairment of myeloid development, SETBP1 and ASXL1 mutations lead to a significant decrease of myeloid differentiation potential with a complete monocytopenia. The prominent loss of myeloid progenitor was associated with a down regulation of myeloid-specific genes and an up-regulation of leukemic stem cell markers. Through epigenomic profiling, we found that mutation in SETBP1 promotes chromatin remodeling in genes involved in myeloid neoplasms that preceded the blockage of myeloid differentiation, a state that persisted after the acquisition of the ASXL1 mutation. Finally, transcription factors motif analysis revealed an enrichment for MEIS1, PU.1, RUNX1 and HOXA9 motifs in more accessible chromatin regions, suggesting their cooperation in disease progression. Beyond establishing a valuable tool for studying the molecular mechanisms underlying GATA2 deficiency, our findings suggest that mutated SETBP1 primes the onset of hematopoietic impairment at transcriptomic and epigenomic level in GATA2 deficiency, a process exacerbated by the acquisition of the ASXL1 mutation.
2025-10-02 | GSE264140 | GEO