Familial myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML), also known as hereditary myeloid malignancy syndromes (HMMSs), have been recognized phenotypically for more than a century, with the first molecular basis discovered in 1999 through the identification of germline RUNX1 mutations [1]. Since then, and recently accelerated by the advent of next-generation sequencing (NGS), a growing number of genes have been associated with germline predisposition to myeloid malignancies, including the ANKRD26 [2,3,4], ETV6 [5,6,7], CEBPA [8], DDX41 [9], GATA2 [10], RBBP6 [11], TERT, TERC [12], and, most recently the SAMD9 [13] and SAMD9L genes [14,15]. Although they are traditionally considered very rare entities, it is now known that 4–13% of pediatric and 5–15% of adult MDS/AML cases are caused by germline predisposition [16,17,18,19,20,21].

Although most of these entities have only recently been described, the World Health Organization (WHO) incorporated some of them as provisional categories in its fourth revised classification [22]. In recognition of the robustness of data, HMMSs have also been integrated into other guidelines and expert recommendations, such as the Nordic Guidelines and the European Leukemia Network [23,24], highlighting the need to identify, diagnose, and correctly manage patients with hereditary syndromes. Finally, the growing recognition and molecular identification of this subset of myeloid malignancies have led to their being formalized in the most recent revisions by the WHO and the International Consensus Classification (ICC) of myeloid neoplasms [25,26]. The WHO 2022 update reinforces this category and includes it within the group of secondary myeloid neoplasms [25]. On the other hand, the 2022 ICC proposes to place these entities within the category of pediatric and/or germline mutation-associated disorders due to their overlap with other childhood disorders [26].

This review focuses on one of these entities, specifically the phenotypic spectrum of patients diagnosed with GATA2 deficiency, recognized as a major myeloid neoplasia predisposition syndrome with pleiotropic manifestations. We discuss the structural characteristics of the GATA2 gene and describe how its genetic alterations might contribute to the onset of myeloid neoplasms as a result of aberrant induced hematopoiesis [27]. In addition, we will summarize diagnostic clues for proper identification and management of this syndrome.

The GATA binding protein 2 (GATA2) gene is located on the long arm of human chromosome 3 at cytoband 21.3 (i.e., 3q21.3) and encodes two main isoforms (NM_032638 and NM_001145661) identical in their coding regions, but differing in the 5′ untranslated region [28,29]. The GATA2 protein belongs to the GATA binding factors family, which modulates the expression of several genes by binding to the DNA motif GATA and other transcription factors [30]. This is managed by two highly conserved zinc finger domains (ZF1 and ZF2), which are responsible for the DNA-binding ability of GATA2. In addition, the GATA2 protein contains two transactivation domains, a nuclear localization signal, and a negative regulatory domain [29].

The precise role of GATA2 in hematopoiesis is still not entirely understood. Hematopoietic stem cells (HSCs) found in the bone marrow of GATA2^+/− mice were found to be impaired in terms of both number and functionality, as evidenced by serial transplantation assays [31]. GATA2 heterozygosity is associated with decreased proliferation ability and increased quiescence and apoptosis in HSCs [31]. Moreover, GATA2 haploinsufficiency impairs the function of granulocyte-macrophage progenitors but not that of other committed myeloid progenitors [32]. Despite this, GATA2^+/− mice do not develop MDS/AML, which makes it challenging to study the impact of GATA2 haploinsufficiency on leukemic progression in these models.

On the other hand, the overexpression of GATA2 results in the self-renewal of myeloid progenitors and hampers lymphoid differentiation in mouse bone marrow [33]. Additionally, the overexpression of GATA2 promotes proliferation in human embryonic stem cells (hESCs) but quiescence in hESC-derived HSCs [34]. Elevated levels of GATA2 have been observed in AML patients, both adults and children, who have poor prognoses [35]. These findings indicate that, in addition to its function as a tumor suppressor, GATA2 may also act as an oncogene when overexpressed.

In line with these data, and focusing on adult hematopoiesis, the GATA2 protein, together with several transcription factors (e.g., FLI1, LMO2, and RUNX1), is involved in HSC survival and self-renewal, thus participating in early lineage commitment. Meanwhile, during hematopoietic differentiation, GATA2 modulates downstream fate decisions by interacting with CEBPA, GATA1, and SPI1 [36,37].

To date, roughly 500 GATA2-deficient patients have been reported, and the syndrome was confirmed to be inherited according to an autosomal dominant pattern in 50% of cases, de novo in 5% of cases, and uncertain in the rest of the cases [38]. This is unexpectedly different from previous studies, in which de novo occurrence was estimated in two thirds of all cases [39,40]. However, there is a lack of a well-characterized series in which segregation studies have been carried out systematically or in which penetrance or expressivity were considered. Therefore, these data should be viewed with caution.

In addition, almost 200 unique (likely) pathogenic variants have been described that can be classified into four groups: truncating mutations (splice site, nonsense, frameshift, and whole-gene deletions) proximal to or within the ZF2 domain; missense mutations within the ZF2 domain; mutations resulting in aberrant mRNA splicing (e.g., synonymous changes) (Figure 1) [38,41,42]; and other regulatory variants, such as those located in the GATA2 intronic +9.5 kb enhancer site (e.g., c.1017+572C>T, the c.1017+532A>T, and the c.1017+513_1017+540del [c.1017+512del28]), which is essential for hematopoiesis [42,43,44,45,46]. Overall, germline GATA2 (likely) pathogenic variants are hypothesized to result in haploinsufficiency because truncated alleles lead to clinical phenotypes similar to missense variants [31,45]. Strikingly, some variants have been associated with only partial loss-of-function (p.T354M) or even gain-of-function (p.L359V) mechanisms, suggesting more complex pathways [47,48].

Although most deleterious changes are private, it is possible to recognize some mutational hotspots. Recurrent variants in the extended ZF2 domain have been identified, including p.T354M and p.R396W/Q/W, found in roughly one fifth of the reported cases, as well as the c.1017+572C>T intronic variant, found in 20 patients [38].

Germline GATA2 mutations are usually necessary but not sufficient for myeloid disease development. It has been proposed that different environmental stressors may modify the expression of these germline variants during embryogenesis or after birth, inducing disorder in tissues where limited GATA2 expression is inadequate for their normal cellular function [38]. Particularly in bone marrow (BM), such stressors can lead to certain cytogenetic and molecular alterations that accumulate over time, selecting clonality and triggering myeloid transformation. Indeed, the germline variant can also modify the BM microenvironment, contributing to clonal selection [38].

In patients with progression to a malignant neoplasm, certain cytogenetic and molecular alterations appear recurrently. The most frequent cytogenetic alterations in patients with germline GATA2-mutated myeloid neoplasms involve chromosome 7, including its monosomy, partial deletion of 7q and der(1;7)(q10;p10), and trisomy of chromosome 8 [27,40,49]. These neoplasms tend to show fewer somatic mutations and a different molecular landscape compared to non-GATA2 MDS/AML. The most frequent recurrent somatic mutations identified in GATA2-MDS/AML patients are in the SETBP1, ASXL1, and STAG2 genes, and the RAS pathway. By contrast, deleterious SF3B1, U2AF1, NPM1, and FLT3 changes are infrequent in GATA2-mutated myeloid neoplasms [21,50,51,52,53,54,55,56,57,58,59,60].

Interestingly, GATA2 can also be mutated in somatic cells of sporadic MDS/AML. Different from germline GATA2 mutations, which mainly include truncated and ZF2 missense changes, somatic GATA2 mutations are usually missense variants located in the ZF1 domain (e.g., p.N317-L321 hotspot) or in-frame indels in the C-terminus (Figure 1) [38]. This suggests a likely difference in GATA2 function during the leukemogenic process between germline and somatic cases [61]. Of note, somatic GATA2 mutations are often associated with both monoallelic and biallelic CEBPA somatic mutations [62,63,64]. Additionally, somatic mutations in GATA2, although rare, have also been linked to milder forms of the immunodeficiency phenotype observed in patients with germline mutant GATA2 [65,66].

Heterozygous pathogenic variants in the GATA2 gene cause a highly heterogeneous disorder with incomplete penetrance [67]. This may present with immunodeficiency (including monocytopenia with Mycobacterium avium complex (MonoMAC) infection and dendritic cell (DC), monocyte, B, and natural killer (NK) lymphoid (DCML) deficiency syndromes); syndromic features, such as congenital deafness and lymphedema (originally defining Emberger syndrome), or pulmonary and vascular involvement [49], and there is a high probability of evolving to MDS and/or AML. In 2011, these diverse clinical syndromes were linked to define a common genetic diagnosis of the GATA2 deficiency syndrome [10,45,68,69].

Except for a few cases, the relationship between genotype and phenotype in these patients is poorly understood due to significant variations in clinical presentation, even among individuals within the same family [41,49]. Therefore, determining the true clinical penetrance of this disorder would require a comprehensive examination of the genotypes of a large number of first-degree relatives of patients. It is worth noting some of the reported phenotype/genotype correlations: (1) patients with noncoding variants (which can account for up to 10% of cases) have been observed to exhibit reduced disease penetrance [41,49,70,71]; (2) the p.T354M variant seemed to be associated with a predominance of myeloid malignancies (83% of cases; 44/53), while p.R398W/Q variants were more commonly associated with immunodeficiency (88% of cases; 23/26) in a relatively large series [38]; (3) there have been indications that complete haploinsufficiency or loss of GATA2 function, rather than missense mutations, may be required for the development of lymphedema [72].

These complex and variable presentations pose a significant challenge for clinicians when diagnosing and managing patients with GATA2 mutations.

The first hematoimmunologic manifestation typically occurs between the second and third decade of life, with a median age that varies in different studies (ranging from 12 to 19 years) [38,39,41,49,71]. While some patients present with cytopenias, immunodeficiency, or BM failure during childhood, others can develop MDS without preexisting clinical features during young adulthood (Figure 2) [27].

GATA2 deficiency is a unique primary immune deficiency that is also known as immunodeficiency 21, DCML, or MonoMAC (OMIM #614172). The immune defect may appear in adult life, as the number of hematopoietic stem and progenitor cells (HSPCs) decreases with age, which makes GATA2 deficiency a unique primary immune deficiency [80]. It is characterized by immunophenotype features resembling those seen in chronic infection or age-related immunosenescence. The spectrum of alterations can include dendritic cell deficiency, monocytopenia, loss of transitional B cells, the absence of CD56 bright NK cells (which presents an altered CXCL12/CXCR4-dependent chemotaxis [76,81,82,83,84]), reversed CD4:CD8 ratio, an excess of CD45RA+ CD8+ T cells, and poor-quality humoral response [27,85] despite normal levels of immunoglobulins and an adequate presence of bone marrow plasma cells in most patients [40,86,87].

As a result of immune deficiency, GATA2 carriers have an increased frequency of infections, with significant differences in the severity between patients [80]. Due to the deficit and dysfunction of dendritic cells, NK cells, and monocytes/macrophages, the identification of viruses and intracellular pathogens is compromised, leading to the severe spread of viral infections and mycobacterial susceptibility [40,41]. Donadieu and colleagues described severe bacterial infections as the most frequent pathogenic occurrences in GATA2 carriers, with a cumulative rate of 33% at 20 years and 64% at 40 years [71]. On the other hand, Spinner et al. reported that severe viral infections were the most common ones in their series (70%), in particular those related to the human papilloma virus (HPV), which occurred in about two thirds of carriers [41]. The most important complication derived from underlying HPV infection is the development of recurrent warts or condyloma that can lead to dysplasia and/or squamous carcinoma [88]. Infections with other disseminated pathogens are frequently observed in GATA2-deficient patients, including non-tuberculous mycobacteria, herpes virus (varicella zoster virus, Epstein–Barr virus, and cytomegalovirus), and fungi (invasive aspergillosis, disseminated histoplasmosis, and candidiasis) [41].

Therefore, various immunological factors are highly suggestive of GATA2 deficiency and should make the clinician think of this disorder. These include prior immunodeficiency in a patient with MDS, atypical mycobacterial infections in patients with monocytopenia, persistent warts or severe herpes virus infections in cytopenic patients, and loss of B cells and their precursors, especially in patients who develop MDS [27,41,84,85].

Eventually, as in other immunodeficiencies, these patients can also present with autoimmune manifestations, described in 11–30% of cases [41,71,89], which may overshadow typical features of GATA2 deficiency and delay the diagnosis. Amarnani et al. reported rheumatological findings in 18% of their GATA2 deficiency cohort, with notable manifestations, including early onset osteoarthritis, piezogenic pedal papules, ankylosing spondylitis, and seronegative erosive rheumatoid arthritis [89].

Recognizing GATA2 deficiency in clinical care is crucial for several reasons [115]. Firstly, an accurate diagnosis can help patients understand their specific disorder and avoid inappropriate treatments. Secondly, a genetic diagnosis can aid in selecting the most suitable HSCs donor for an allo-HSCT. TShirdly, identifying GATA2 syndrome can impact treatment recommendations and disease management for patients and their families. As patients with this condition face various complications affecting many systems, HSCT is often an attractive therapeutic option. The choice of therapy largely depends on the patient´s age, the availability of a compatible donor, and any co-existing medical conditions. Thus, early and accurate diagnosis of these patients allows for tailored therapy.

As awareness of GATA2 deficiency grows within the scientific community, early diagnosis will help in avoiding unnecessary diagnostic procedures and enable tailored strategies, for both treatment and surveillance [49].

Moreover, we may be able to identify patients who are at high risk of transforming to myeloid malignancies based on factors such as molecular alterations, cytogenetic evolution, or severity of cytopenias. By managing these patients early, we can aim for better outcomes before organ dysfunction occurs.

M.S.; writing—original draft preparation, M.S., A.L., E.S., Á.Z. and J.C.; writing—review and editing, J.C.; supervision. All authors have read and agreed to the published version of the manuscript.

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The authors declare no conflict of interest.

This study was supported by research funding from FEDER funds (CIBERONC [CB16/12/00284]), Instituto de Salud Carlos III (ISCIII) grants PI18/1472, PI19/00812, and PI22/01633, Fundació La Marató de TV3 grant 228/C/2020, as well as from the Conselleria de Educación, Cultura y Deporte CIGE/2021/015. M.S. is the recipient of the “Clinico Junior 2019” (CLJUN19005SANT) and Rio Hortega (CM22/00191) fellowships granted by the Asociación Española contra el Cáncer (AECC) and the ISCIII, respectively. A.L. is the recipient of the APOSTD/2021/212 Generalitat Valenciana post-doctoral fellowship.