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J. Donadieu et al.
40. Eighteen patients developed acute or chronic leukemia. In addition, we identified a second patient with acute lymphoblastic leukemia (ALL).23 The GATA2 tran- scription factor is crucial for hematopoietic stem cell self- renewal and differentiation,24,25 but also for B- and T-cell development in vitro, as shown in a recent murine low- level GATA2 overexpression model.26 Only 4 of 18 patients survived (2 after HSCT, one after azacitidine treatment, one JMML). Most of the other 14 died from infections and/or progressive hematologic disease. Long- term survival of our cohort is poor, with a high rate of mortality (probability of 42% at the age of 40, 69% at the age of 60). Classic chemotherapy strategies were revealed to be toxic and poorly efficient, and HSCT is hampered by the very high rates of toxicity in these patients.
Early deaths were caused by the association of hemato- logic malignancies with severe infections. We propose to identify the patients at risk of evolution towards leukemia using the IPSS-R score.21 Moreover, secondary somatic mutations occur, which leads to leukemic transformation in patients with a GATA2 mutation. ASXL1 mutations were implicated in the first reports,27,28 then mutations in the RAS pathway and in the AML/MDS mutated genes.29 Some patients have a long history of low-risk MDS before it evolves into an aggressive disease, thus underlying the importance of identifying the markers that precede this hematologic evolution to help clinicians. Importantly, our study showed that the earlier HSCT is performed, the bet- ter the outcome. The question of timing of pre-emptive transplantation is still a subject of debate, but the improved overall survival of patients with refractory cytopenias sug- gests that early HSCT is a reasonable approach. Identification of additional somatic mutation in patients with MDS may prompt clinicians to perform HSCT.
Our series confirmed the heterogeneity of the GATA2 mutational spectrum, with 45 different alleles including 26 new mutations. The previously published series have not reported correlations between genotype and phenotype, with the exception of null mutants which seems to be associated with an increased risk of lymphoedema in the US cohort.13 In our cohort, patients with missense muta- tions had a higher risk of developing leukemia than patients with frameshift or nonsense mutations. These data may suggest that the translated mutated GATA2 pro- tein resulting from missense mutations is dominant nega- tive and/or promotes leukemogenesis in contrast to frameshift or nonsense mutations, which may lead to hap- loinsufficiency. Recently, Chong et al. reported that the most prevalent GATA2 missense mutations (gT354M, gR396Q and gR398W) exhibit differences in the age of leukemia onset, supporting the concept of different func- tional consequences of GATA2 mutants.30 Our observation is reported for the first time and may also help clinicians to choose the best therapeutic option, especially an aggressive treatment for the disease. Further functional studies are needed to demonstrate this hypothesis.
Severe and recurrent bacterial infections are frequent at diagnosis, and persist throughout the patient’s life. A mild defect of immunoglobulin production or a weak vaccinal response had also been reported in patients with a GATA2 deficiency.31 There is a lower incidence of mycobacterial diseases in our cohort (40% of the patients at the age of 40) than previously reported,13,14 occurring after the age of 20 in the majority of patients.
All patients with mycobacterial disease have abnormal blood counts, monocytopenia (10 of 16), MDS (9 of 15) or both (7 of 15). The relatively low frequency of mycobacterial infection may be explained by the severi- ty of disseminated infection leading to death or drastic treatment (such as HSCT) to avoid recurrence. Some patients experienced successive diseases with different species of environmental mycobacteria, suggesting that immunological memory is not efficient in patients with GATA2 mutations. Fungal infections occurred in 18 patients. Aspergillosis was always associated with neu- tropenia, as a consequence of GATA2 deficiency or sec- ondary to the chemotherapy.
Multiple cutaneous and genital warts at presentation are frequent (32 patients). Recurrent and life-threatening oncogenic HPV lesions led us to recommend early HPV vaccination, as proposed in WILD syndrome,32,33 which is maybe a clinical variant of GATA2 deficiency.34 Interestingly, one patient developed new HPV lesions after HSCT, raising the question of HPV genome persistence in epithelial cells, or a specific role for GATA2 in ker- atinocytes in the host control of HPV. It suggests that early HPV vaccination should be proposed in mutated patients. Susceptibility to severe viral infections led to 4 deaths in our cohort. One patient died from PML caused by the JC virus as the first manifestation of GATA2 deficiency; NK cell deficiency,35 monocytopenia and dendritic cell defi- ciency5 probably contribute to this immunodeficiency.
New clinical presentations were identified in our survey. Auto-immune or chronic inflammatory disorders, such as lupus, sarcoidosis-like disease, Sweet's syndrome, panni- culitis are recurrent. Lupus-like symptoms and autoim- mune hepatitis have also been described in GATA2 defi- ciency.14,36 Given the occurrence of mycobacterial disease, infection should be investigated in patients with proven granuloma.
Beyond the marked clinical heterogeneity of GATA2 deficiency, we also described 5 asymptomatic cases, including that of a 60-year old patient, raising the possibil- ity that clinical penetrance is not complete. To evaluate clinical penetrance, genotypes of all first degree relatives of patients must be available. Moreover, these observa- tions should lead to systematically testing a potential rela- tive considered for donation when an HSCT with a sibling donor is feasible.
This multicenter study was a unique opportunity to provide an extended and detailed clinical picture of GATA2 deficiency, which is a severe disorder that com- bines immunodeficiency, hematologic malignancy, pul- monary, dermatological and vascular diseases. It highlight- ed the fact that patients with GATA2 missense mutations have a high risk of developing leukemia and that this may be prevented by early HSCT with the help of new mark- ers (identification of additional somatic mutations).
Acknowledgments
The Authors thank the patients and families for their partici- pation in this study. The French registry is supported by grants from Amgen SAS, Chugai SA, Novartis, and by a grant from the Inserm. This project is supported by grants from Associations Laurette Fugain, 111 les Arts, Société Française des Cancers de l’Enfant, Enfanfare, Association Sportive de Saint Quentin Fallavier, and Barth France. The Authors thank the association IRIS for its support.
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