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GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis

The GATA binding protein 2 (GATA2) belongs to the GATA family of transcription factors, which contain zinc fingers in their DNA binding domain. The human GATA2 gene, located on 3q21, is encoded by six exons and contains a conserved DNA-binding domain composed of two multifunctional zinc finger domains (ZFDs). GATA2 is an indispensable transcription factor for hematopoiesis as it maintains the proliferative progenitor-cell phenotype. Its downregulation is necessary for differentiation and thus GATA2 expression is tightly regulated by several transcription factors such as NOTCH1, PU.1 and EVI1 as well as by the cytokines IL-1 and TNFα.1 As GATA2 has been shown to have a key role in controlling the proliferation and differentiation of hematopoietic cells, defects arising from mutations in this gene may contribute to hematopoietic disorders, including leukemia.

So far, there are few studies analyzing the role of GATA2 in hematological malignancies. Zhang et al.2 analyzed genetic alterations of transcription factors in 85 cases of BC-CML (chronic myeloid leukemia in blast crisis) and, among others, identified two mutations in GATA2: a p.Leu359Val substitution within the C-terminal ZFD of GATA2 was found in eight cases with myelomonoblastic features, whereas an in-frame deletion of six amino acids (D341–346) spanning the C-terminal border of the C-terminal ZFD was detected in one patient demonstrating myeloid BC with eosinophilia. Further studies indicated that GATA2 Leu359Val not only increased transactivation activity of GATA2 but also enhanced its inhibitory effects on the activity of PU.1, a major transcription factor for myeloid cell differentiation, via aberrant protein–protein interaction.2 Furthermore, heterogeneous GATA2 mutations (GATA2mut) have been described in families with predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).3, 4 GATA2mut in these diseases are presumed to differentially affect binding of other proteins, leading to variable consequences on target gene regulation and cell fate determination. Interestingly, two mutations were repeatedly found in different syndromes associated with AML and MDS: p.Thr354Met and p.Thr355del.3 Recently, GATA2mut have also been described in a single study with a frequency of 40.6% in a cohort of 32 CN-AML (cytogenetically normal AML) patients with biallelic CEBPA gene mutations.5, 6 All GATA2mut were missense mutations and were located in the N-terminal ZFD.

On the basis of the previously mentioned study,5, 6 we first evaluated GATA2mut in intermediate-risk karyotype AML with biallelic CEBPA (biCEBPA) mutations for frequency, association with other mutations and impact on outcome. We therefore analyzed 98 such cases for GATA2mut by direct Sanger Sequencing of exons 4 and 5, which contain the two highly conserved N-and C-terminal ZFDs of GATA2. Additionally, we screened 22 intermediate-risk karyotype AML cases with monoallelic CEBPA (monoCEBPA) mutations and 92 cases with CEBPA wild-type (CEBPAwt) for GATA2mut. The study design adhered to the tenets of the Declaration of Helsinki and was approved by our institutional review board before its initiation. GATA2 mutation analysis was performed on either bone marrow or peripheral blood samples. Sanger sequencing of GATA2 exons 4 and 5 was performed following RT–PCR using the following primers: GATA2_Ex4-F: 5′-IndexTermGGTTAAGCAGGCCCCCGTGTC-3′, GATA2_Ex4-R: 5′-IndexTermATTAACCGCCAGCTCCTGCC-3′, GATA2_Ex5-F: 5′-IndexTermCAGCCTGCTGACGCTGCCTT-3′, GATA2_Ex5-R: 5′-IndexTermGCCTCTTGCCTGGCAGCACA-3′. Mutation status of other genes was available as follows: NPM1: n=212, FLT3-ITD: n=212, CEBPA: n=212, MLL-PTD: n=211, RUNX1: n=211, ASXL1: n=212, FLT3-TKD: n=210, WT1: n=211. In all, 156 cases (73.6%) were CN-AML and 56 (26.4%) had intermediate-risk aberrant cytogenetics according to Medical Research Council criteria.7 Female/male ratio was 107/105 and age ranged from 15.7 to 84.9 years (median: 59.7) (Table 1).

Table 1 Demographics and clinical and molecular characteristics of AML patients according to GATA2 mutations status

Overall, in 21/212 patients (9.9%) GATA2mut were detected. However, as the total cohort was not unselected the frequency was calculated separately for the biCEBPA (n=18/98, 18.3%) and the CEBPAwt cohort (n=3/92, 3.3%). All mutations were point mutations. In detail, most mutations (n=14, 66.7%) were located in the N-terminal ZFD (aa 294–344). Five patients harbored a mutation in the C-terminal ZFD (aa 349–398). One patient had two mutations in the N-terminal ZFD and one patient had each one mutation in both the N-and C-terminal ZFDs, respectively (Figure 1a; Table 2). Of note, no patient harbored the mutations reported in BC-CML or familial AML-MDS, suggesting a different oncogenic mechanism in these diseases. All mutations were analyzed by PolyPhen prediction ( and were identified as probably damaging indicating a loss of GATA2 function. This result is in contrast to GATA2mut found in BC-CML that have been described as gain of function mutations resulting in enhanced DNA binding and co-activator recruitment and furthermore have been shown to result in repression of the myeloid master regulator PU.1.

Figure 1

(a) Distribution of GATA2 mutations within the N- and C-terminal ZFDs detected within the total cohort of 212 patients. Numbers in circles below the indicated mutations indicate the frequency of the respective mutations. If no number is given, then the mutation was observed once. (b) Alignment of gene mutations for 212 patients. Each column represents one of the 212 analyzed samples. Mutations in the nine investigated genes are shown by colored bars. A red bar indicates a mutation; a gray bar, no mutation; whereas a white bar indicates that no data were available. (c) Concomitant events of GATA2 with other mutations are also shown as a bar chart. The gray part represents GATA2wt, the red one GATA2mut within the analyzed subcohorts. GATA2mut frequencies and significances (P-values) are denoted; numbers of mutated/analyzed cases of the subcohorts are given in parenthesis below the bars.

Table 2 GATA2 mutations detected within the total cohort of 212 patients

GATA2mut tended to be more frequent in females than in males (n=15/107, 14.0% vs 6/105, 5.7%, P=0.064). There was no association with age, leukocyte count, hemoglobin level, platelet count or cytogenetics (Table 1). In 103 cases, immunophenotyping data were available. Cases with GATA2mut (n=10) had a higher expression of CD133 (52±29% vs 29±27%, P=0.015), CD34 (67±30% vs 42±31%, P=0.018) and HLA-DR (59±28% vs 38±24%, P=0.017) as well as lower expression of CD11b (19±14% vs 37±24%, P=0.003) and CD36 (10±5% vs 23±15%, P<0.001) and thus had a more immature phenotype as compared with GATA2wt. With regard to cytomorphology, we observed a preponderance of AML M1 (n=12/21) and AML M2 (n=8/21) subtypes in GATA2mut cases. In addition, GATA2mut were strongly associated with biCEBPA mutations (n=18/98 18.3% vs 3/92, 3.3% in CEBPAwt, P<0.001), whereas GATA2mut were mutually exclusive of monoCEBPA mutations (0/22; P=0.041) and of FLT3-ITD (0/45; P=0.009) (Figure 1b). Furthermore, we observed GATA2mut in three patients without biCEBPA mutations. Two of these patients had an additional NPM1 mutation and the third patient harbored a mutation in RUNX1.

As GATA2 has been described to be an MDS/AML predisposing gene and germline mutations were reported,3, 4 we analyzed remission samples of 10/21 GATA2mut cases. In all 10 cases the GATA2mut detected at initial diagnosis were not detectable in remission and thus was somatic and not germline (Supplementary Table 1). In four GATA2mut patients, sample material was available at diagnosis, remission and also at relapse. Two patients carried additional biCEBPA mutations at diagnosis, one patient showed an additional NPM1 mutation and one patient showed additional mutations in NPM1, WT1 and NRAS. Only the patient with the additional NPM1 mutation showed the same GATA2 mutation at both diagnosis and first relapse. In the other three patients, the GATA2mut were absent at relapse (Supplementary Table 2). This strongly suggests GATA2mut as secondary events.

Clinical follow-up data were available in 194/212 patients and in 20/21 patients with GATA2mut. With regard to prognosis, patients with GATA2mut had significantly better 2-year overall survival (2y-OS) (100% vs 53.1%, P=0.001) and 2-year event free survival (EFS) (63.8% vs 35.7%, P=0.025) compared with GATA2wt cases (Figures 2a and b). In univariable analysis, GATA2mut were associated with better EFS (P=0.03) and OS (P=0.041). However, in multivariable analysis GATA2mut lost their impact on EFS and OS (Supplementary Table 3). Because of the high coincidence of GATA2 and biCEPBA mutations, the prognostic impact of GATA2mut in dependence on biCEBPA mutations was analyzed. Patients with biCEBPA mutations and additional GATA2mut (n=17) had a better 2-year OS compared with patients with biCEBPA mutations and GATA2wt (n=63) (100% vs 76.1% P=0.058) (Figure 2c). Interestingly, GATA2 had been shown to interact with CEPBA by forming protein complexes and this interaction is critical for the suppression of adipocyte differentiation.8 Thus, the coincidence of mutations in both genes could impair interaction and provoke a differentiation advantage of these cells resulting in the favorable prognosis of patients harboring both GATA2mut and biCEBPA mutations.

Figure 2

Kaplan Meier survival analysis of 194 intermediate-risk AML patients. (a) OS within the total cohort 194 patients. Data are shown for GATA2 mutated patients (n=20) and GATA2 wild-type patients (n=174; alive at 2 years: 100.0% vs 53.1%). (b) EFS within the total cohort 194 patients. Data are shown for GATA2 mutated patients (n=20) and GATA2 wild-type patients (n=174; alive at 2 years: 63.8% vs 35.7%). (c) OS within 80 patients with biCEBPA mutations. Data are shown for biCEBPA mutated/GATA2 mutated patients (n=17) and biCEBPA mutated/GATA2 wild-type patients (n=63; alive at 2 years: 100.0% vs 76.1%). (d) EFS within 80 patients with biCEBPA mutations. Data are shown for biCEBPA-mutated/GATA2-mutated patients (n=17) and biCEBPA-mutated/GATA2-wild-type patients (n=63; alive at 2 years: 63.8% vs 49.2%).

In conclusion, we confirmed a strong association of GATA2mut with biCEBPA mutations in a large set of intermediate-risk AML patients. Furthermore, we did not observe GATA2mut in patients with monoCEPBA mutations underlining the different biology of AML with biallelic vs monoCEPBA mutated AML. For the first time, this study also provides data on the frequency of GATA2mut in CEPBAwt AML, in which a low frequency of only 3.3% was detected. Analyses performed at relapse demonstrated that GATA2mut are secondary events. Furthermore, GATA2mut are associated with female sex and favorable impact on survival. GATA2 thus seems to be a promising new marker to identify patients with even more favorable prognosis in the subgroup of patients with the prognostically favorable biCEBPA mutated AML.


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We thank all clinicians for sending samples to our laboratory for diagnostic purposes, and for providing clinical information and follow-up data. In addition, we would like to thank all co-workers at the MLL Munich Leukemia Laboratory for approaching together many aspects in the field of leukemia diagnostics and research. Especially the technical assistance of Madlen Ulke, who performed Sanger Sequencing analyses, is greatly appreciated. In addition, we are grateful for the data management support performed by Tamara Alpermann.

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Correspondence to S Schnittger.

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CH, WK, TH and SuS are equity owners of and AF, CE, VG, AK and FD are employed by the MLL Munich Leukemia Laboratory.

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Supplementary Information accompanies the paper on the Leukemia website

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Fasan, A., Eder, C., Haferlach, C. et al. GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia 27, 482–485 (2013).

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