Explore the vast range of titles available.

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p  = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.

Patients with GATA2 deficiency are predisposed to developing myelodysplastic neoplasms (MDS), which can progress to acute myeloid leukemia. This progression is often associated with cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are recurrently observed in GATA2 patients, although their roles remain poorly understood. Here we develop a hiPSC-based system to investigate the impact of SETBP1 and ASXL1 mutations in GATA2 deficiency. Using precise genome editing, we recreate stepwise mutational trajectories observed in GATA2-related MDS. We demonstrate that GATA2 mutation has limited impact on hematopoietic progenitors, while the co-occurrence of SETBP1 or ASXL1 mutations impairs myeloid differentiation. The combination of all three mutations severely depletes myeloid progenitors, recapitulating GATA2-related MDS and highlighting their synergistic interplay. Notably, SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes an iPSC-based model of GATA2 deficiency, offering new insights into myeloid disease progression and a platform for testing future therapeutic strategies. GATA2 deficiency is one of the major causes of hereditary pediatric myelodysplastic neoplasms (MDS). Using iPSC-based models, this work recapitulates stepwise mutational trajectories in GATA2-related MDS and reveals their impact on myeloid differentiation.

Purpose GATA2 deficiency, a rare inborn error of immunity, presents with highly variable phenotypes. Bone marrow (BM) changes such as hypocellularity and myelodysplastic syndrome (MDS) are common, with hematopoietic stem cell transplantation being the only curative option due to the risk of progression to acute myeloid leukemia. Although traditional markers like cytogenetic abnormalities and somatic mutations (e.g., ASXL1 ) identify the risk of leukemic transformation, efforts to identify novel predictors of disease evolution are needed. CD8+ T cells are known to play a key role in MDS immune surveillance, but their specific involvement in GATA2 deficiency remains poorly defined. Methods In this case report, we report on a young adult with GATA2 deficiency who underwent longitudinal monitoring of both peripheral and BM lymphocyte subsets, with a focus on CD8+ T-cell evolution in relation to MDS progression. Results The patient exhibited typical GATA2-deficient immune-hematological findings, including monocytopenia, B- and NK-cell deficiency, but had no history of severe infections and remained transfusion-independent. While peripheral CD8+ T-cell levels remained stable over time, a notable reduction in BM CD8+ T cells was observed in association with MDS progression. Conclusion Providing a long-term follow-up of one GATA2-deficient patient, we suggest that a decrease in BM CD8+ T cells may serve as an early marker of immune surveillance escape and disease progression. These findings underscore the need for further investigation into the role of BM CD8+ T cells in GATA2 deficiency and MDS evolution, potentially offering new insights for follow-up and therapeutic intervention.

The atypical cadherin FAT4 has established roles in the regulation of planar cell polarity and Hippo pathway signaling that are cell context dependent. The recent identification of FAT4 mutations in Hennekam syndrome, features of which include lymphedema, lymphangiectasia, and mental retardation, uncovered an important role for FAT4 in the lymphatic vasculature. Hennekam syndrome is also caused by mutations in collagen and calcium binding EGF domains 1 (CCBE1) and ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3), encoding a matrix protein and protease, respectively, that regulate activity of the key prolymphangiogenic VEGF-C/VEGFR3 signaling axis by facilitating the proteolytic cleavage and activation of VEGF-C. The fact that FAT4, CCBE1, and ADAMTS3 mutations underlie Hennekam syndrome suggested that all 3 genes might function in a common pathway. We identified FAT4 as a target gene of GATA-binding protein 2 (GATA2), a key transcriptional regulator of lymphatic vascular development and, in particular, lymphatic vessel valve development. Here, we demonstrate that FAT4 functions in a lymphatic endothelial cell-autonomous manner to control cell polarity in response to flow and is required for lymphatic vessel morphogenesis throughout development. Our data reveal a crucial role for FAT4 in lymphangiogenesis and shed light on the mechanistic basis by which FAT4 mutations underlie a human lymphedema syndrome.

The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonically lethal, a single-nucleotide Ets motif mutant was viable, and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics, in which a disease predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis.

GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. 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 describe a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2 . While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, 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 hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that Gata2 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 and altered pool of HSCs 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.

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation’s impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age. These include increased LT-HSC numbers, reduced self-renewal potential, and impaired response to acute inflammatory stimuli. The mature HSPC compartment was primarily affected at the CMP sub-population level. In the mutant LT-HSC population, we identified an aberrant subpopulation strongly expressing CD150, resembling aging, but occurring prematurely. This population showed hyporesponsiveness, accumulated over time, and exhibited allele-specific expression (ASE) favoring the mutated Gata2 allele, also observed in GATA2 mutated patients. Our findings reveal the detrimental impact of a Gata2 recurrent missense mutation on the HSC compartment contributing to its functional decline. Defects in the CMP mature compartment, along with the inflammatory molecular signature, explain the loss of heterogeneity in HPC compartment observed in patients. Finally, our study provides a valuable model that recapitulates the ASE-related pathology observed in GATA2 deficiency, shedding light on the mechanisms contributing to the disease’s natural progression.

Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.