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GATA2 Mutations Are Frequent in Intermediate-Risk Karyotype AML with Biallelic CEBPA Mutations and Are Associated with Favorable Prognosis

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GATA2 Mutations Are Frequent in Intermediate-Risk Karyotype AML with Biallelic CEBPA Mutations and Are Associated with Favorable Prognosis Leukemia (2013) 27, 482–516 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu LETTERS TO THE EDITOR GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis Leukemia (2013) 27, 482–485; doi:10.1038/leu.2012.174 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 The GATA binding protein 2 (GATA2) belongs to the GATA family following RT–PCR using the following primers: GATA2_Ex4-F: of transcription factors, which contain zinc fingers in their DNA 50-GGTTAAGCAGGCCCCCGTGTC-30, GATA2_Ex4-R: 50-ATTAACCGCC binding domain. The human GATA2 gene, located on 3q21, is AGCTCCTGCC-30, GATA2_Ex5-F: 50-CAGCCTGCTGACGCTGCCTT-30, encoded by six exons and contains a conserved DNA-binding GATA2_Ex5-R: 50-GCCTCTTGCCTGGCAGCACA-30. Mutation status of domain composed of two multifunctional zinc finger domains other genes was available as follows: NPM1: n ¼ 212, FLT3-ITD: (ZFDs). GATA2 is an indispensable transcription factor for hemato- poiesis as it maintains the proliferative progenitor-cell phenotype. Table 1. Demographics and clinical and molecular characteristics of Its downregulation is necessary for differentiation and thus GATA2 AML patients according to GATA2 mutations status expression is tightly regulated by several transcription factors such as NOTCH1, PU.1 and EVI1 as well as by the cytokines IL-1 Characteristics GATA2wt GATA2mut P and TNFa.1 As GATA2 has been shown to have a key role in (N ¼ 191) (N ¼ 21) controlling the proliferation and differentiation of hematopoietic cells, defects arising from mutations in this gene may contribute No. of %Of No. of %Of patients total patients total to hematopoietic disorders, including leukemia. So far, there are few studies analyzing the role of GATA2 Age (years) in hematological malignancies. Zhang et al.2 analyzed genetic Median 60 54 n.s. Range 16–85 23–83 alterations of transcription factors in 85 cases of BC-CML (chronic myeloid leukemia in blast crisis) and, among others, identified Gender Female 92 43.4 15 7.1 0.064 two mutations in GATA2: a p.Leu359Val substitution within the Male 99 46.7 6 2.8 C-terminal ZFD of GATA2 was found in eight cases with myelomo- FAB subtype (n ¼ 203) n.s. noblastic features, whereas an in-frame deletion of six amino acids M0 2 100.0 0 0.0 (D341–346) spanning the C-terminal border of the C-terminal ZFD M1 78 38.4 12 5.9 was detected in one patient demonstrating myeloid BC with M2 73 36.0 8 3.9 M4 19 100.0 0 0.0 eosinophilia. Further studies indicated that GATA2 Leu359Val not M5 6 100.0 0 0.0 only increased transactivation activity of GATA2 but also enhanced M6 4 89.7 1 10.3 its inhibitory effects on the activity of PU.1, a major transcription Type of disease (n ¼ 212) n.s. factor for myeloid cell differentiation, via aberrant protein–protein de-novo AML 184 86.8 20 9.4 2 t-AML 2 1.0 1 4.8 interaction. Furthermore, heterogeneous GATA2 mutations s-AML 5 2.4 0 0.0 (GATA2mut) have been described in families with predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia Hemoglobin, g/dl (n ¼ 159) n.s. 3,4 Median 9.4 9.3 (AML). GATA2mut in these diseases are presumed to Range 4.0–14.4 7.1–12.1 differentially affect binding of other proteins, leading to variable WBC count, Â 109/L (n ¼ 163) n.s. consequences on target gene regulation and cell fate determi- median 38.1 48.1 nation. Interestingly, two mutations were repeatedly found in Range 1.0–249.5 6.0–182.0 different syndromes associated with AML and MDS: p.Thr354Met 9 3 Platelet count, x10 /L (n ¼ 163) n.s. and p.Thr355del. Recently, GATA2mut have also been described Median 87 56 in a single study with a frequency of 40.6% in a cohort of 32 CN- Range 5–950 9–225 AML (cytogenetically normal AML) patients with biallelic CEBPA Bone marrow blasts, % (n ¼ 187) n.s. gene mutations.5,6 All GATA2mut were missense mutations and Median 62 61 were located in the N-terminal ZFD. Range 4–98 22–90 On the basis of the previously mentioned study,5,6 we first Correlating mutations k evaluated GATA2mut in intermediate-risk karyotype AML with monoCEBPA (n ¼ 22/212) 22 10.4 0 0.0 0.041 biCEBPA (n ¼ 98/212) 80 37.7 18 8.5 o0.001 m biallelic CEBPA (biCEBPA) mutations for frequency, association with NPM1 (n ¼ 45/212) 43 20.3 2 0.9 n.s. other mutations and impact on outcome. We therefore analyzed FLT3-ITD (n ¼ 45/212) 45 21.4 0 0.0 0.009 k FLT3-TKD (n ¼ 4/210) 4 1.9 0 0.0 n.s. 98 such cases for GATA2mut by direct Sanger Sequencing of exons MLL-PTD (n ¼ 14/211) 14 6.6 0 0.0 n.s. 4 and 5, which contain the two highly conserved N-and C-terminal RUNX1 (n ¼ 23/211) 22 10.4 1 0.5 n.s. ASXL1 (n ¼ 31/212) 30 14.2 1 0.5 n.s. ZFDs of GATA2. Additionally, we screened 22 intermediate-risk WT1 (n ¼ 19/211) 17 8.1 2 0.9 n.s. karyotype AML cases with monoallelic CEBPA (monoCEBPA) mutations and 92 cases with CEBPA wild-type (CEBPAwt) for Abbreviations: AML, acute myeloid leukemia; biCEBPA, biallelic CEBPA; FAB, GATA2mut. The study design adhered to the tenets of the French-American-British; monoCEBPA, monoallelic CEBPA; WBC, white blood cell. Significant values are written in bold. Declaration of Helsinki and was approved by our institutional Accepted article preview online 3 July 2012; advance online publication, 20 July 2012 Letters to the editor 483 n ¼ 212, CEBPA: n ¼ 212, MLL-PTD: n ¼ 211, RUNX1: n ¼ 211, ASXL1: count or cytogenetics (Table 1). In 103 cases, immunophenotyping n ¼ 212, FLT3-TKD: n ¼ 210, WT1: n ¼ 211. In all, 156 cases (73.6%) data were available. Cases with GATA2mut (n ¼ 10) had a were CN-AML and 56 (26.4%) had intermediate-risk aberrant higher expression of CD133 (52±29% vs 29±27%, P ¼ 0.015), cytogenetics according to Medical Research Council criteria.7 CD34 (67±30% vs 42±31%, P ¼ 0.018) and HLA-DR (59±28% vs Female/male ratio was 107/105 and age ranged from 15.7 to 38±24%, P ¼ 0.017) as well as lower expression of CD11b 84.9 years (median: 59.7) (Table 1). (19±14% vs 37±24%, P ¼ 0.003) and CD36 (10±5% vs Overall, in 21/212 patients (9.9%) GATA2mut were detected. 23±15%, Po0.001) and thus had a more immature phenotype However, as the total cohort was not unselected the frequency as compared with GATA2wt. With regard to cytomorphology, we was calculated separately for the biCEBPA (n ¼ 18/98, 18.3%) and observed a preponderance of AML M1 (n ¼ 12/21) and AML M2 the CEBPAwt cohort (n ¼ 3/92, 3.3%). All mutations were point (n ¼ 8/21) subtypes in GATA2mut cases. In addition, GATA2mut mutations. In detail, most mutations (n ¼ 14, 66.7%) were located were strongly associated with biCEBPA mutations (n ¼ 18/98 in the N-terminal ZFD (aa 294–344). Five patients harbored a 18.3% vs 3/92, 3.3% in CEBPAwt, Po0.001), whereas GATA2mut mutation in the C-terminal ZFD (aa 349–398). One patient had two were mutually exclusive of monoCEBPA mutations (0/22; mutations in the N-terminal ZFD and one patient had each one P ¼ 0.041) and of FLT3-ITD (0/45; P ¼ 0.009) (Figure 1b). Further- mutation in both the N-and C-terminal ZFDs, respectively more, we observed GATA2mut in three patients without biCEBPA (Figure 1a; Table 2). Of note, no patient harbored the mutations mutations. Two of these patients had an additional NPM1 reported in BC-CML or familial AML-MDS, suggesting a different mutation and the third patient harbored a mutation in RUNX1. oncogenic mechanism in these diseases. All mutations were As GATA2 has been described to be an MDS/AML predisposing analyzed by PolyPhen prediction (http://genetics.bwh.harvard. gene and germline mutations were reported,3,4 we analyzed edu/pph2/) and were identified as probably damaging indicating remission samples of 10/21 GATA2mut cases. In all 10 cases the a loss of GATA2 function. This result is in contrast to GATA2mut GATA2mut detected at initial diagnosis were not detectable in found in BC-CML that have been described as gain of function remission and thus was somatic and not germline (Supplementary mutations resulting in enhanced DNA binding and co-activator Table 1). In four GATA2mut patients, sample material was available recruitment and furthermore have been shown to result in at diagnosis, remission and also at relapse. Two patients carried repression of the myeloid master regulator PU.1. additional biCEBPA mutations at diagnosis, one patient showed an GATA2mut tended to be more frequent in females than in males additional NPM1 mutation and one patient showed additional (n ¼ 15/107, 14.0% vs 6/105, 5.7%, P ¼ 0.064). There was no mutations in NPM1, WT1 and NRAS. Only the patient with the association with age, leukocyte count, hemoglobin level, platelet additional NPM1 mutation showed the same GATA2 mutation at 294 Exon 4 344 349Exon 5 398 ZFD 1 ZFD 2 His GIn lle His Pro Ser Val Arg Lvs GIn GIn Leu Asp Phe 361 379 317 321 308 317 318 321 354 362 329 307 320 321 As Arg Leu Ala Arg Thr Leu Arg Gly Arg Leu Asn Asn Leu wild-type mutated CEBPA biallelic CEBPA monoallelic no data available 120 GATA2 mut 18.4% GATA2 wt 100 80 60 4.4% 40 3.2% 4.3% 10.5% Total case numbers 20 0 monoCEBPA biCEBPA FLT3-ITD NPM1 MLL-PTD RUNX1 WT1 FLT3 -TKD ASXL1 (0/22) (18/98) (0/45) (2/45) (0/14) (1/23) (2/19) (0/4) (1/31) p=0.041 p<0.001 p=0.009 Case Numbers (GATA2 mut/positive cases) Figure 1.
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