ABSTRACT
In their paper, using zebrafish models, Gioacchino et al. have demonstrated the GATA2 haploinsufficiency, the genetic hallmark of GATA2 deficiency syndrome, promotes erythroid and myeloid cytopenia, and have discovered a self-regulatory mechanism to compensate GATA2 levels and protein function. Commentary on: Gioacchino et al. GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia. Br J Haematol 2024;205:580-593.
Subject(s)
GATA2 Deficiency , GATA2 Transcription Factor , Zebrafish , GATA2 Deficiency/genetics , Animals , Zebrafish/genetics , Humans , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/deficiency , Haploinsufficiency , Disease Models, Animal , Epigenesis, GeneticABSTRACT
BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology. CASE PRESENTATION: Three patients with HLH, one with Mycobacterium avium infection, one with Epstein-Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing. CONCLUSIONS: GATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.
Subject(s)
GATA2 Deficiency , GATA2 Transcription Factor , Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/genetics , GATA2 Deficiency/genetics , GATA2 Deficiency/complications , Male , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/deficiency , Female , Epstein-Barr Virus Infections/complications , AdultABSTRACT
T cell receptor repertoire sequencing (TCRseq) has become one of the major omic tools to study the immune system in health and disease. Multiple commercial solutions are currently available, greatly facilitating the implementation of this complex method into translational studies. However, the flexibility of these methods to react to suboptimal sample material is still limited. In a clinical research context, limited sample availability and/or unbalanced sample material can negatively impact the feasibility and quality of such analyses. We sequenced the T cell receptor repertoires of three healthy controls and four patients with GATA2 deficiency using a commercially available TCRseq kit and thereby (1) assessed the impact of suboptimal sample quality and (2) implemented a subsampling strategy to react to biased sample input quantity. Applying these strategies, we did not find significant differences in the global T cell receptor repertoire characteristics such as V and J gene usage, CDR3 junction length and repertoire diversity of GATA2-deficient patients compared with healthy control samples. Our results prove the adaptability of this TCRseq protocol to the analysis of unbalanced sample material and provide encouraging evidence for use of this method in future studies despite suboptimal patient samples.
Subject(s)
GATA2 Transcription Factor , Receptors, Antigen, T-Cell , Humans , GATA2 Transcription Factor/deficiency , GATA2 Transcription Factor/genetics , High-Throughput Nucleotide Sequencing , Receptors, Antigen, T-Cell/geneticsABSTRACT
Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
Subject(s)
Cytogenetic Analysis , GATA2 Transcription Factor/deficiency , GATA2 Transcription Factor/genetics , Leukemia, Myeloid/genetics , Penetrance , Siblings , Adolescent , Adult , Base Sequence , Child , Fatal Outcome , Female , Humans , Leukemia, Myeloid/diagnostic imaging , Male , PedigreeABSTRACT
A 9-year-old girl was admitted to the paediatric intensive care unit with acute respiratory failure due to influenza. Nine months earlier, she presented with unexplained lymphoedema of the lower extremities and monocytopenia. She had a history of occasional finger warts and onychomycoses. During hospitalisation, the patient was diagnosed with Emberger syndrome caused by GATA2 deficiency. The admission was complicated by thromboses in the right hand, leading to amputation of multiple fingers. From then on, the patient has been in good recovery, the function of her right hand was improving and an allogeneic haematopoietic cell transplantation has now been successfully performed.
Subject(s)
Fingers/pathology , GATA2 Deficiency/complications , GATA2 Transcription Factor/deficiency , Influenza A virus/immunology , Respiratory Distress Syndrome/immunology , Amputation, Surgical , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Child , Codon, Nonsense , DNA Mutational Analysis , Drug Therapy, Combination , Female , Fingers/surgery , GATA2 Deficiency/diagnosis , GATA2 Deficiency/genetics , GATA2 Deficiency/immunology , GATA2 Transcription Factor/genetics , Gangrene/immunology , Gangrene/surgery , Glucocorticoids/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Influenza A virus/isolation & purification , Influenza, Human/complications , Influenza, Human/immunology , Influenza, Human/therapy , Influenza, Human/virology , Lung/diagnostic imaging , Lung/immunology , Respiration, Artificial , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/therapy , Severity of Illness Index , Tomography, X-Ray ComputedSubject(s)
Frameshift Mutation , GATA2 Deficiency , GATA2 Transcription Factor/deficiency , Lymphedema , Myelodysplastic Syndromes , Adult , GATA2 Deficiency/genetics , GATA2 Deficiency/metabolism , GATA2 Deficiency/pathology , Humans , Lymphedema/genetics , Lymphedema/metabolism , Lymphedema/pathology , Male , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolismABSTRACT
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.
Subject(s)
GATA2 Deficiency/genetics , GATA2 Transcription Factor/deficiency , GATA2 Transcription Factor/genetics , RNA/genetics , Silent Mutation/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Association Studies , Genetic Predisposition to Disease/genetics , Germ-Line Mutation/genetics , Heterozygote , Humans , Immunologic Deficiency Syndromes/genetics , Male , Myelodysplastic Syndromes/genetics , Phenotype , Young AdultABSTRACT
Genetic susceptibility to myelodysplastic syndrome (MDS) occurs in children with inherited bone marrow failure syndromes, including Fanconi anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Available evidence (although not perfect) supports annual surveillance of the blood count and bone marrow in affected persons. Optimal treatment of MDS in these persons is most commonly transplantation. Careful consideration must be given to host susceptibility to DNA damage when selecting a transplant strategy, because significant dose reductions and avoidance of radiation are necessary. Transplantation before evolution to acute myeloid leukemia (AML) is optimal, because outcomes of AML are extremely poor. Children and adults can present with germline mutations in GATA2 and RUNX1, both of which are associated with a 30% to 40% chance of evolution to MDS. GATA2 deficiency may be associated with a clinically important degree of immune suppression, which can cause severe infections that can complicate transplant strategies. GATA2 and RUNX1 deficiency is not associated with host susceptibility to DNA damage, and therefore, conventional treatment strategies for MDS and AML can be used. RUNX1 deficiency has a highly variable phenotype, and MDS can occur in childhood and later in adulthood within the same families, making annual surveillance with marrow examination burdensome; however, such strategies should be discussed with affected persons, allowing an informed choice.
Subject(s)
Genetic Predisposition to Disease , Monitoring, Physiologic , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Adolescent , Core Binding Factor Alpha 2 Subunit/genetics , Female , GATA2 Transcription Factor/deficiency , GATA2 Transcription Factor/genetics , Germ-Line Mutation/genetics , HumansABSTRACT
BACKGROUND: Patients with GATA2 deficiency present with nontuberculous mycobacterial infections, severe viral infections (particularly refractory human papillomavirus disease), lymphedema, myelodysplastic syndrome (MDS), and acute myeloid leukemia. Patients with GATA2 deficiency who undergo allogeneic hematopoietic stem cell transplantation prior to the development of life-threatening infections or cytogenetic abnormalities may have optimal clinical outcomes. OBJECTIVES: The aim of this article is to determine ways in which oncology nurses can identify GATA2 deficiency in patients early and optimize treatment decisions. METHODS: A case study is presented of a 33-year-old man with recurrent infections and MDS and his two sons, all of whom were found to have the same GATA2 mutation. FINDINGS: Oncology nurses play an important role in early detection and identification by interviewing patients and obtaining a complete and thorough family history.
Subject(s)
GATA2 Transcription Factor/deficiency , Myelodysplastic Syndromes/therapy , Treatment Outcome , Adult , Female , Hematopoietic Stem Cell Transplantation , Humans , Male , Myelodysplastic Syndromes/nursing , Oncology NursingABSTRACT
MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2, characterized by multilineage cytopenia with malignant complications and severe infections, including mycobacteria and herpesviruses. We describe the clinical presentation, genetics and antiviral inflammatory responses in a small case series. Two patients presented in childhood with mycobacterial infection and were diagnosed with MonoMAC germline GATA2 variants; their healthy fathers with the same mutations were also studied. Three patients were elderly individuals with acquired GATA2 mutations and malignant haematological conditions. Overall, this study demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by GATA2 mutations.
Subject(s)
GATA2 Transcription Factor/deficiency , Herpesviridae/immunology , Immunologic Deficiency Syndromes/diagnosis , Adult , Child , Female , Humans , Immunologic Deficiency Syndromes/pathology , Ligands , Male , Young AdultABSTRACT
The establishment of the peristaltic machinery of the ureter is precisely controlled to cope with the onset of urine production in the fetal kidney. Retinoic acid (RA) has been identified as a signal that maintains the mesenchymal progenitors of the contractile smooth muscle cells (SMCs), while WNTs, SHH, and BMP4 induce their differentiation. How the activity of the underlying signalling pathways is controlled in time, space, and quantity to activate coordinately the SMC programme is poorly understood. Here, we provide evidence that the Zn-finger transcription factor GATA2 is involved in this crosstalk. In mice, Gata2 is expressed in the undifferentiated ureteric mesenchyme under control of RA signalling. Conditional deletion of Gata2 by a Tbx18cre driver results in hydroureter formation at birth, associated with a loss of differentiated SMCs. Analysis at earlier stages and in explant cultures revealed that SMC differentiation is not abrogated but delayed and that dilated ureters can partially regain peristaltic activity when relieved of urine pressure. Molecular analysis identified increased RA signalling as one factor contributing to the delay in SMC differentiation, possibly caused by reduced direct transcriptional activation of Cyp26a1, which encodes an RA-degrading enzyme. Our study identified GATA2 as a feedback inhibitor of RA signalling important for precise onset of ureteric SMC differentiation, and suggests that in a subset of cases of human congenital ureter dilatations, temporary relief of urine pressure may ameliorate the differentiation status of the SMC coat. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Cell Differentiation , GATA2 Transcription Factor/deficiency , Mesoderm/embryology , Myocytes, Smooth Muscle/physiology , Ureter/embryology , Ureteral Diseases/embryology , Animals , Biomarkers/metabolism , Female , GATA2 Transcription Factor/genetics , Male , Mesoderm/metabolism , Mice , Signal Transduction , Tretinoin/metabolism , Ureter/abnormalities , Ureter/metabolism , Ureteral Diseases/congenital , Ureteral Diseases/metabolismABSTRACT
Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.
Subject(s)
GATA2 Transcription Factor/deficiency , Hematopoietic Stem Cell Transplantation , Immune Reconstitution Inflammatory Syndrome/etiology , Immunologic Deficiency Syndromes/therapy , Mycobacterium Infections, Nontuberculous/etiology , Adolescent , Adult , Allografts , Child , Child, Preschool , Disease Susceptibility , Female , Humans , Immunologic Deficiency Syndromes/genetics , Male , Middle Aged , Mycobacterium Infections, Nontuberculous/immunology , Mycobacterium Infections, Nontuberculous/pathology , Mycobacterium abscessus/isolation & purification , Myelodysplastic Syndromes/etiology , Peripheral Blood Stem Cell Transplantation , Pulmonary Embolism/etiology , Skin Ulcer/etiology , Warts/etiology , Young AdultABSTRACT
PURPOSE: To describe controlled ovarian stimulation (COS) in a population of women with GATA2 deficiency, a genetic bone marrow failure syndrome, prior to allogeneic hematopoietic stem cell transplant METHODS: This is a retrospective case series of nine women with GATA2 deficiency who underwent oocyte preservation at a research institution. Main outcomes measured include baseline fertility characteristics ((antimullerian hormone (AMH) and day 3 follicle-stimulating hormone (FSH) and estradiol (E2)) and total doses of FSH and human menopausal gonadotropins (HMG), E2 on day of trigger, and total number of metaphase II oocytes retrieved. RESULTS: The mean age was 24 years [16-32], mean AMH was 5.2 ng/mL [0.7-10], and day 3 mean FSH was 5.1 U/L [0.7-8.1], and E2 was 31.5 pg/mL [< 5-45]. The mean dose of FSH was 1774 IU [675-4035], and HMG was 1412 IU [375-2925] with a mean E2 of 2267 pg/mL [60.7-4030] on day of trigger. The mean total of metaphase II oocytes was 7.7 [0-15]. One patient was diagnosed with a deep vein thrombosis (DVT) with pulmonary embolism (PE) during COS. CONCLUSION: This study is the first to analyze the outcomes of COS in women with GATA2 deficiency. The response to ovarian stimulation suggests that oocyte cryopreservation should be considered prior to gonadotoxic therapy. However, due to the risk of potentially life-threatening complications, it is prudent that patients are properly counseled of the risks and are evaluated by a multi-disciplinary medical team prior to COS.
Subject(s)
GATA2 Transcription Factor/deficiency , Oocytes/metabolism , Oocytes/physiology , Adolescent , Adult , Anti-Mullerian Hormone/metabolism , Cryopreservation/methods , Estradiol/metabolism , Female , Fertility/physiology , Fertility Preservation/methods , Fertilization in Vitro/methods , Follicle Stimulating Hormone/metabolism , Humans , Oocyte Retrieval/methods , Ovulation Induction/methods , Retrospective Studies , Young AdultABSTRACT
GATA2 deficiency is a recently described genetic disorder affecting hematopoietic stem cells and is associated with immunodeficiency, hematologic malignancy, and various cutaneous pathologies including cutaneous tumors. To explore the incidence and clinical course of melanoma in patients with germline GATA2 deficiencies, we conducted a retrospective chart review of 71 such patients and identified two with invasive melanoma. One melanoma was diagnosed early because it was associated with pruritus due to a graft-versus-tumor effect following bone marrow transplantation. The other one, a lentigo maligna melanoma, was locally excised but progressed to widespread metastasis and death several years later. Our observations and published studies of melanoma biology suggest an association between decreased GATA2 expression and melanoma progression. These findings suggest that GATA2 deficient patients may have an increased risk of melanoma and should be observed closely for new or changing skin lesions.
Subject(s)
GATA2 Transcription Factor/deficiency , Melanoma/metabolism , Female , GATA2 Transcription Factor/metabolism , Humans , Melanoma/diagnosis , Melanoma/pathology , Models, Biological , Risk FactorsABSTRACT
The GATA2 gene codes for a master hematopoietic transcription factor that is essential for the proliferation and maintenance of hematopoietic stem and progenitor cells. Heterozygous germline mutations in GATA2 have been initially associated with several clinical entities that are now collectively defined as GATA2 deficiency. Despite pleiotropic clinical manifestations, the high propensity for the development of myelodysplastic syndromes (MDS) constitutes the most common clinical denominator of this major MDS predisposition syndrome. The immunological phenotypes can be variable and mostly include deficiency of monocytes and/or B cells. Thus far, nearly 380 GATA2-deficient patients had been reported, with a roughly estimated prevalence of myeloid neoplasia of at least 75%. The most common abnormal karyotypes associated with GATA2-related MDS are monosomy 7, der(1;7) and trisomy 8. The overall clinical penetrance seems to be nearly complete for this transcriptopathy disorder. The high-risk MDS subtypes and karyotypes, and the underlying immunodeficiency guide decision-making toward timely stem cell transplantation.
Subject(s)
GATA2 Transcription Factor/deficiency , GATA2 Transcription Factor/genetics , Genetic Association Studies , Germ-Line Mutation/genetics , Myelodysplastic Syndromes/genetics , Chromosome Deletion , Chromosomes, Human, Pair 7 , Chromosomes, Human, Pair 8 , Hematopoiesis/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells , Humans , Myelodysplastic Syndromes/immunology , TrisomyABSTRACT
The GATA2 gene codes for a hematopoietic transcription factor that through its two zinc fingers (ZF) can occupy GATA-DNA motifs in a countless number of genes. It is crucial for the proliferation and maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations in GATA2 were reported in several hundred patients with various phenotypes ranging from mild cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4+ cells, monocytes and dendritic cells (MonoMAC/DCML), and myeloid neoplasia. Some patients additionally show syndromic features such as congenital deafness and lymphedema (originally defining the Emberger syndrome) or pulmonary disease and vascular problems. The common clinical denominator in all reported cohorts is the propensity for myeloid neoplasia (myelodysplastic syndrome [MDS], myeloproliferative neoplasms [MPN], chronic myelomonocytic leukemia [CMML], acute myeloid leukemia [AML]) with an overall prevalence of approximately 75% and a median age of onset of roughly 20 years. Three major mutational types are encountered in GATA2-deficient patients: truncating mutations prior to ZF2, missense mutations within ZF2, and noncoding variants in the +9.5kb regulatory region of GATA2. Recurrent somatic lesions comprise monosomy 7 and trisomy 8 karyotypes and mutations in SETBP1 and ASXL1 genes. The high risk for progression to advanced myeloid neoplasia and life-threatening infectious complications guide decision-making towards timely stem cell transplantation.
Subject(s)
GATA2 Transcription Factor/deficiency , Genetic Predisposition to Disease/genetics , Hematologic Neoplasms/genetics , Myeloproliferative Disorders/genetics , GATA2 Transcription Factor/genetics , HumansABSTRACT
Patients with GATA2 (Emberger syndrome) deficiency needs early hematopoietic stem cell transplant (HSCT) before evolving in to myelodysplastic syndrome or acute myeloid leukemia and with time given compromised organ dysfunction leads to increase regimen-related toxicities. Most published cases have used nonmyeloablative conditioning regimens, show higher incidences of rejection and relapse rates and umbilical cord blood transplant has been reported to be suboptimal in patients with GATA2 deficiency because of longer period of engraftment leads to more infections and mortality. We report a 4.5-year-old girl with GATA2 deficiency who underwent matched unrelated donor HSCT utilizing a myeloablative conditioning regimen including intravenous busulfan (total dose of 12.8 mg/kg) and fludarabine (total dose of 160 mg/m) She tolerated the conditioning regimen and bone marrow infusion well. Her initial chimerism was mixed (90% donor), cyclosporine was gradually weaned and discontinued at day+85 and this resulted in conversion to full-donor chimerism. Bone marrow assessment 3 months post-HSCT revealed normal hematopoiesis and absence of monosomy 7. At 20 months of follow-up she had full-donor chimerism with complete reconstitution of the all hematopoietic stem cells. Myeloablative matched unrelated donor HSCT represents an effective option for cure in patients with GATA2 deficiency and Emberger syndrome.