Heterogeneity of GATA2-related myeloid neoplasms
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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.
KeywordsFamilial MDS Germline predisposition GATA2
Historically, familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) with nonsyndromic manifestation have been occasionally described in association with monosomy 7 karyotypes . Germline mutations in genes coding for transcription factors CEBPA and RUNX1 were discovered as the cause of autosomal dominant familial MDS/AML syndromes, but the genetic cause remained obscure in many reported pedigrees. In 2011, loss-of-function (LOF) mutations or deletions in the GATA2 gene were identified as the third major MDS/AML predisposition syndrome . Strikingly, at almost same time, germline GATA2 mutations were brought in association with other clinical entities, namely the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome , dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency  and primary lymphedema associated with predisposition to acute myeloid leukemia (Emberger syndrome) . Finally, GATA2 deficiency had been identified as the most common known genetic cause of primary childhood MDS, where the majority of affected cases had negative family history . Today, it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease.
Patients with inherited bone marrow failure disorders (IBMFS) such as Fanconi anemia and severe congenital neutropenia have an increased risk of MDS/AML, and a differential diagnosis of IBMFS is important for treatment stratification . From this point of view, the exclusion of germline GATA2 mutations and other familial MDS/AML predisposition syndromes clearly also has an impact on therapy recommendations and family counseling. These aspects are now addressed in a new chapter on myeloid neoplasms with germ line predisposition, included in the 2016 revision of the WHO classification of hematological malignancies .
In this review, we summarize key information on myeloid neoplasms originating from germline GATA2 mutation.
Role of GATA2 in normal and malignant hematopoiesis
Genetic causes of GATA2 deficiency
Clinical phenotype of GATA2 deficiency
Non-hematologic disease spectrum
Systemic infections: mycobacterial (non-tuberculous), fungal, viral (herpesviruses)
HPV-associated disease: generalized warts, intra-epithelial neoplasia
Autoimmune manifestations (i.e., lupus-like, AIHA, ITP, arthritis, hepatitis)
Pulmonary alveolar proteinosis, BOOP-like disease, abnormal lung function
Lymphedema: extremities, genital (hydrocele), cellulitis
Thrombosis (deep vein)
Hypotelorism, epicanthis folds, uni/bilateral ptosis
Urogenital malformations (VUR, kidney asymmetry, hymen imperforatum)
Behavioral problems, autism spectrum disorders, chronic headache
Dysmorphic features can be present in some but not all affected patients, and include congenital deafness, facial anomalies, urogenital malformations; behavioral problems such as autism spectrum disorders can be also present. Other non-hematologic disease manifestation is variable: some patients may develop pulmonary problems, autoimmune symptoms (e.g., lupus-like disease, immune cytopenias), thrombosis, and generalized warts and HPV-related cancers (Table 1). In summary, hematopoietic, immune, lymphatic, vascular, urogenital, and neurological systems can be affected by GATA2 deficiency. The overall penetrance for hematologic malignancy is very high, and for the occurrence of any of the specific disease symptoms is nearly complete.
MonoMAC syndrome/DCML deficiency
Immunodeficiency was the leading medical problem in the initial cohorts described with GATA2 mutations: autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome , dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency  with predisposition to MDS/AML. Generalized warts related to HPV infection were common viral complication, in addition to severe HSV, VZV, EBV and CMV infections. Disseminated non-tuberculous mycobacteria (NTM) infections were observed in about half of cases with MonoMAC syndrome . Severe bacterial or fungal infections, and pulmonary alveolar proteinosis (PAP) were also prevalent in MonoMAC syndrome. Notably, after HSCT, the rates of infections and PAP can significantly decrease .
The association of primary lymphedema and predisposition to MDS/AML with or without congenital deafness by autosomal dominant inheritance was reported by Emberger et al. . Germline GATA2 mutations were identified as a single common denominator by whole exome sequencing . GATA2 protein is expressed at high levels in endothelial cells and lymphatic vessel valves [26, 27] and controls the expression of PROX1 and FOXC2 genes important for programming lymphatic valve development . In one study, it has been suggested that N-terminal frameshift mutations or larger deletions of GATA2 are more likely to cause lymphedema ; however, this association could not be confirmed in other patient cohorts . Congenital deafness is presumed to result from failure of generation of the perilymphatic space surrounding the semicircular ducts in inner ear .
Germline GATA2 mutations were detected in four pedigrees with an autosomal dominant inheritance pattern of MDS/AML in 2011 . Variable clinical manifestations were shown in large pedigrees . It is not understood, however, why some patients develop MDS while carriers of identical mutations in the same family do not develop relevant hematologic symptoms.
Our group has screened more than 600 cases of primary or secondary MDS in children and adolescents who were enrolled in the European Working Group of MDS in childhood. The overall frequency of germline GATA2 mutations was 15% for advanced and 7% for all primary MDS cases. Surprisingly, 72% of adolescents diagnosed with MDS and monosomy 7 harbor germline mutations in GATA2. Conversely, mutations were absent in the group with secondary MDS that was therapy related or occurred after aplastic anemia. We propose that GATA2 screening should be included in the workup of all children and young adults with monosomy 7, trisomy 8, or independent of karyotype if presenting with features suspicious for GATA2 deficiency [6, 31]. Interestingly, in pediatric MDS cohorts, not monocytopenia but B-cell lymphopenia (including progenitors in bone marrow) was identified as the most consistent immunological feature [32, 33]. This might be due to the fact that true functional monocytopenia might be masked by the expansion of malignant myelo-monocytic lineage in the setting of MDS with monosomy 7.
Monocytopenia has been previously proposed as a diagnostic feature of GATA2 deficiency. However, some patients with GATA2-related MDS can present with monocytosis rather than monocytopenia [6, 34]. Somatic ASXL1 mutations are associated with the presence of monosomy 7, BM hypercellularity and CMML . Furthermore, several (rare) cases of adult CMML disease were reported in germline GATA2 mutation carriers. GATA2 deficiency seems not to play a role in the pathogenesis of JMML .
GATA2 deficiency-associated bone marrow disorder can present with features overlapping with aplastic anemia. Distinguishing GATA2 patients from aplastic anemia is critical for selecting appropriate therapy. Four out of 32 patients with suspected aplastic anemia who had features suspicious for GATA2 mutations were identified by DNA sequencing .
The analysis of patients enrolled in the French Severe Chronic Neutropenia Registry identified 7 pedigrees with germline GATA2 mutations who presented with mild chronic neutropenia associated with immunodeficiency and subsequent MDS evolution .
Acquired genetic abnormalities in carriers of germline GATA2 mutations
The mechanism of malignant clonal evolution in GATA2-deficient patients is not understood. First, recurrent karyotype abnormalities involving chromosomes 7 and 8 point to their mechanistic relevance in context of underlying GATA2 deficiency. However, these cytogenetic aberrations are not specific to GATA2 deficiency, as they also can arise in MDS originating from hereditary predisposition syndromes . Second, recurrent loss-of-function ASXL1 mutations have been described in patients with GATA2 deficiency. However, the presence of ASXL1 mutations seems to be determined by the underlying karyotype, namely monosomy 7 . This most frequent karyotype in pediatric is associated with ASXL1 and SETBP1 mutations, independently of germline GATA2 mutational status [34, 41]. Similarly to ASXL1, the presence of somatic SETBP1 mutations in GATA2-related MDS seems to be associated with monosomy 7 . From functional perspective, the association of SETBP1-ASXL1 mutations was postulated as a cooperative mechanism advancing leukemic transformation . Finally, recurrent mutations in STAG2 gene were identified in several cases with GATA2 deficiency; however, the functional significance is not known [41, 44, 45].
Treatment of myeloid neoplasms with germline GATA2 mutations
Because the phenotypic heterogeneity is not only evident between different non-related carriers of the same mutation, but also within a single family, it is difficult giving advice on the individual outcomes and recommending tailored treatment strategies. Nevertheless, early diagnosis of GATA2 deficiency can help to avoid unnecessary or toxic therapies, for example, prolonged immunosuppression or AML-type chemotherapy given for advanced MDS. Overall, non-curative therapies should be limited and because of the high risk for evolution of advanced MDS with unfavorable karyotypes, timely HSCT should be suggested as a curative approach. Overall survival (OS) of GATA2-mutated patients transplanted for immunodeficiency was shown to be 54% at 4 years after transplantation in a NIH-based study . In pediatric GATA2 cohorts, 5-year OS was 66% in patients transplanted for MDS with monosomy 7. Notably, OS and outcome of HSCT were not influenced by GATA2 mutational status . Our findings indicate that GATA2 deficiency itself does not increase transplant-related mortality in affected children (most of the patients received myeloablative regimen due to monosomy 7). Ideally, HSCT should be performed before the development of MDS with excess of blasts, cytogenetic clone, and oncogenic somatic mutations. These factors support the need for a close monitoring of GATA2 mutation carriers for the occurrence of any of these events.
GATA2 deficiency belongs to the disease group of transcriptopathies predisposing to myeloid neoplasia. The heterogenous clinical manifestation, ranging from immunodeficiency, vascular phenotypes, deafness, to sporadic myeloid neoplasia illustrates the pleiotropic function of this master transcription factor. However, many important questions remain unanswered at present. For example, it is not known what drives the development of delayed onset myeloid neoplasia in GATA2-haploinsufficient background. Among many hypotheses, one could speculate that either a chronic pathogen challenge might be toxic to the BM and result in leukemic transformation, or GATA2 deficiency itself results in dose perturbation of other transcription factors such as RUNX1 or PU1 which themselves can act as oncogenes. Another question is what determines the variable clinical expressivity where in one family several affected carriers display varying phenotypes and develop MDS at different age. Thus far, there is no evidence of revertant somatic mosaicism (such as encountered in Fanconi anemia) in GATA2 deficiency; however, other mechanisms that control the rate of allelic expression might be the cause, e.g., epigenetic modulation. Several of these questions should be answered in prospective international studies.
SH is supported by St. Luke's Life Science Institute Grant.
SH and MWW wrote the paper, EK and CMN contributed with conception and figures.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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