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Overexpression of GATA2 predicts an adverse prognosis for patients with acute myeloid leukemia and it is associated with distinct molecular abnormalities

Leukemia volume 26, pages 550–554 (2012)Cite this article

Acute myeloid leukemia (AML) represents a heterogeneous group of hematological neoplasms associated with the accumulation of acquired genetic and epigenetic aberrations in hematopoietic progenitor cells. Myeloid leukemogenesis is directly linked to the disruption of expression of transcription factors that regulate the proliferation, survival and differentiation of myeloid progenitors. Moreover, overexpression of particular genes has been associated with prognosis in AML, enabling patients with different survival rates to be identified within cytogenetic risk groups. The GATA2 gene encodes a transcription factor that mediates essential functions in hematopoietic stem cell and progenitor cell (HSC/HPC) compartments. The essential role of GATA2 in hematopoiesis is evident in mice lacking GATA2, which are anemic, have fewer HSC/HPC cells and that die by day 10–11 of gestation.1 Expression of GATA2 is critical at various stages of hematopoiesis, and as it in part determines the fate of distinct myeloid lineages, GATA2 expression is tightly regulated. Indeed, ectopic expression of GATA2 has been reported to promote erythroblast proliferation while blocking terminal erythroid differentiation.2 Furthermore, alterations in GATA2 expression have been observed in patients with myelodysplastic syndrome, where it has been related to severe dysplasia.3 Nevertheless, to date, only two studies have analyzed the expression of GATA2 in AML. Strong GATA2 expression was found in 87% of AML patients (54/62) using single-round RT-PCR.4 More recently, Ayala et al.5 analyzed the expression of GATA2 in 41 patients with AML by real-time quantitative RT-PCR (QRT-PCR). They found that 21 cases had expression of GATA2 (52%), and defined overexpression as the expression values that were over the median value in GATA2-expressing patients. Therefore, to further clarify the significance of GATA2 overexpression in AML, we investigated its prevalence in a large series of AML patients using QRT-PCR. Furthermore, using an established cutoff value, we correlated these results with cytogenetic data and molecular markers, and we determined the prognostic relevance of GATA2 expression levels. GATA2 expression was analyzed in bone marrow samples from 259 AML patients referred for analysis to the University of Navarra (Spain). Gene expression was quantified using the ABI Prism 7500 Real Time PCR System and TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA, USA), with GAPDH as an internal control. A gene was considered to be overexpressed if its expression level was greater than the established cutoff value determined for each gene (mean±3 s.d.), defined by the analysis of 10 bone marrow samples from normal donors. Statistical analyses were performed using the SPSS software package (v.15, SPSS Inc., Chicago, IL, USA). More detailed information about the molecular and statistical analyses performed is provided in the Supplementary Information.

Using the calculated cutoff value for GATA2 expression, we divided patients into two groups: ‘cases with overexpression of GATA2’ and ‘cases with no GATA2 overexpression’. With this approach, we found that GATA2 was overexpressed in 37.4% of cases (97/259), suggesting that this could be a recurrent event in AML (Table 1 and Supplementary Figure 1). Thus, for the first time we showed the prevalence of GATA2 overexpression in a large cohort of AML patients using QRT-PCR. The possible association between GATA2 expression and other biological features was analyzed using the χ2-test or the Fisher's exact test, as appropriate, for categorical variables, and the Mann–Whitney test for continuous variables. We found that GATA2 overexpression was associated with clinical and biological features that confer poor prognosis in AML. Accordingly, GATA2 overexpression was more prevalent in the poor cytogenetic risk group (46%), in elderly patients (P=0.056), in those with secondary AML (P=0.054), and in patients overexpressing WT1 (P<0.001) and EVI1 (P<0.001) (Table 1). These data support previous findings demonstrating a role for GATA2 as an enhancer of WT1 transcription, and describing a positive correlation between GATA2 and WT1 messenger RNA (mRNA) levels.6 Furthermore, EVI1 has been shown to bind directly to the GATA2 promoter and act as an enhancer, suggesting that GATA2 represents a critical target of EVI1.7 High levels of GATA2 expression have been associated with myeloid neoplasms involving 3q rearrangements.8 When we analyzed the 20 patients with 3q rearrangements by fluorescence in situ hybridization, EVI1 was overexpressed in the nine patients with 3q21 and/or 3q26 aberrations (two 3q21 rearrangements, six 3q26 and one 3q21q26). With the exception of two cases with 3q26 aberrations, GATA2 was overexpressed in seven of these nine cases. Thus, the majority of patients overexpressed both GATA2 (3q21) and EVI1 (3q26) (7/9, 77.8%). These data would indicate that GATA2 contributes as a downstream target gene of EVI1 to the leukemic transformation of EVI1-positive AML, an issue that merits further investigation.

Table 1 Prevalence of GATA2 overexpression in 259 patients with acute myeloid leukemia at diagnosis, and its association with cytogenetic and molecular markers
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Acknowledgements

This study was supported by Fondo de Investigación Sanitaria (FIS) del Instituto Carlos III (FI05/00497), Ministerio Educación y Ciencia (SAF2005/06425), Ministerio Ciencia e Innovación (PI081687), Departamento Salud del Gobierno de Navarra (14/2008), ISCIII-RTICC (RD06/0020/0078) and Fundación para la Investigación Médica Aplicada y UTE (Spain). We thank María J Larráyoz for technical assistance.

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  1. Division of Oncology, Laboratory of Genetics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    C Vicente, I Vazquez, A Conchillo, M A García-Sánchez, N Marcotegui & M D Odero

  2. Department of Genetics, University of Navarra, Pamplona, Spain

    C Vicente, M J Calasanz & M D Odero

  3. Department of Medical Pathology, Hospital Universitario La Fe, Valencia, Spain

    O Fuster

  4. Department of Hematology, Hospital Universitario, Salamanca, Spain

    M González

  5. Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium,

    I Lahortiga

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Vicente, C., Vazquez, I., Conchillo, A. et al. Overexpression of GATA2 predicts an adverse prognosis for patients with acute myeloid leukemia and it is associated with distinct molecular abnormalities. Leukemia 26, 550–554 (2012). https://doi.org/10.1038/leu.2011.235

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