GATA2 mutation

In the intermediate-risk group, the high median VAF of GATA2 (≥38.51%) had no significant effect in OS and RFS compared with the low median VAF (<38.51%). This study offers new insights on the prognosis of GATA2mut in the favorable-risk group, where VAF can be used as a guide.

P2, N=144, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025

P2, N=144, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2023 --> Dec 2024

However, the percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but, unlike in MDS, does not predict survival.

P2, N=40, Recruiting, Fred Hutchinson Cancer Center

Most of germline GATA2 mutation carriers will have symptoms in young age and many of them will progress into malignant myeloid diseases. Allo-HSCT was effective to treat symptomatic patients, especially for patients with malignant hematologic diseases, and furthermore that is the only curative treatment. Asymptomatic carriers are not rare and for them regular tests are essential.

The detailed description of how GATA2 regulates HSC maintenance and blood lineage determination is crucial to unravel the pathogenesis of GATA2 deficiency syndrome. In this review, we summarize current advances in elucidating the role of GATA2 in hematopoietic cell fate determination and discuss the challenges of modeling GATA2 deficiency syndrome.

However, percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but unlike in MDS does not predict survival.

P2, N=32, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Clinicians should be aware that patients with GATA2 PVs could be vulnerable to opportunistic IFIs, even in the absence of AML and antineoplastic therapy. Furthermore, the distinctly unusual occurrence of mucormycosis during the first course of induction chemotherapy for AML in our patient indicates that patients with germline GATA2 PVs receiving induction chemotherapy for AML might be at high risk for early onset of IFIs due to aggressive, opportunistic moulds.

Busulfan/melphalan was the most frequent conditioning regimen (58%)...Recent retrospective data have shown a benefit of post-transplantation cyclophosphamide (PTCy) in GATA2 patients transplanted with sibling or matched unrelated donors (Nichols‐Vinueza et al... This retrospective study reports the outcomes of 84 patients who underwent allo-HCT for childhood MDS. This study seems to show a benefit associated with the pre-transplant cytoreduction therapy in the subgroup of patients with cMDS-IB, notably through a reduction of aGVHD and NRM occurrence. BuCyMel conditioning, currently recommended for cMDS-IB, appears here, to be associated with excess of toxic mortality.

P=N/A, N=150, Recruiting, Institut Claudius Regaud | Not yet recruiting --> Recruiting

P2, N=120, Recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial primary completion date: Jun 2024 --> Dec 2025

This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream regulatory enhancer element in patients with MonoMAC syndrome. Patients in this study were enrolled in National Institute of Allergy and Infectious Diseases clinical trial Clinicaltrials.gov identifier NCT01905826 and National Cancer Institute clinical trial Clinicaltrials.gov identifier NCT01861106.

This compilation of tests confirmed MDS with multilineage dysplasia and patient was discharged with oncology follow up to begin Azacytidine treatment (Table 1)... MDS is not considered as the first differential for a young 21 year old patient presenting with pancytopenia but our case shows the importance in cytogenetic and molecular testing workup in diagnosing rare syndrome of MDS in young adults. Early diagnosis in our patient led to early start of treatment with chemotherapy as well as stem cell transplant referral.

P2, N=120, Recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial primary completion date: Jun 2023 --> Jun 2024

A recent report of 59 patients with GATA2 deficiency who underwent allogenic HCT with myeloablative, busulfan-based conditioning and post-transplant cyclophosphamide reported excellent overall and event-free survival of 85% and 82% with reversal of disease phenotype and low rates of graft versus host disease. Allogeneic HCT with myeloablative conditioning results in disease correction and should be considered for patients with a history of recurrent, disfiguring and/or severe infections, organ dysfunction, MDS with cytogenetic abnormalities, high-risk somatic mutations or transfusion dependence, or myeloid progression. Improved genotype/phenotype correlations are needed to allow for greater predictive capabilities.

P2, N=32, Not yet recruiting, National Cancer Institute (NCI)

Thus, Gata2a maintains myeloid lineage priming through cebpa and protects against genome instability and marrow failure by maintaining expression of npm1a. Our results establish a potential mechanism underlying bone marrow failure in GATA2 deficiency.

Refractory or relapsed AML (R/RAML) patients with CEBPAdmnonbZIP were associated with shorter OS compared to those with CEBPAdmbZIP (HR = 2.881, 95% CI = 1.021-8.131, P = .046). Taken together, AML with CEBPAdmbZIP and CEBPAdmnonbZIP showed different outcomes and might be regarded as distinctive AML entities.

Integration of NGS has refined prognosis and clinical management of patients. Nevertheless, some patients with normal karyotype in our study was found to have poor prognosis mutations. TET2 mutation was helpful for the decision of treatment with HMA even in the older patients.

In summary, we developed a new in vivo human model of GATA2 deficiency and GATA2-MDS-specific mutations by CRISPR/Cas9 targeting of CD34+ cells. Our findings strongly suggest that GATA2 R398W mutation is not sufficient to increase the fitness of the mutant cells, suggesting that a co-operation of genetic, epigenetic andstressor factors is necessary to trigger the clonal expansion. MDS/AML, GATA-2, Pediatric, Mouse model

We identified an aberrant DNA hypermethylated signature in GATA2 deficiency. Specifically, we described the presence of a subset of aberrant hypermethylated set of genes present in GATA2 carriers at early disease stage,which could be potentially used as predictors of clonal evolution. GATA-2, Genetic, MDS/AML, Epigenetic

Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

P2, N=37, Recruiting, Franziska Wachter | Not yet recruiting --> Recruiting

P2, N=37, Not yet recruiting, Franziska Wachter

Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/haematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians for their management of patients, but also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.

To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.

As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency including: 1) why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2, 2) what are the genetic changes that lead to myeloid progression, 3) what causes the apparent genetic anticipation, and 4) what is the role of preemptive HSCT.

We are currently investigating what are the factors contributing to engraftment and AEL development in AML samples with bi-allelic CEBPA mutation and GATA2 zinc finger-1 mutation.Our studies suggests engraftment of CEBPA mutant AML samples depend on the subclass of CEBPA mutation and secondary mutation present in the AML sample. This knowledge of differential engraftment of CEBPA mutant sample in NSGS mice offers a valuable model for testing novel therapies for CEBPA mutant AML.

Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.