HIGH GATA2 EXPRESSION IS A POOR PROGNOSTIC MARKER IN PEDIATRIC ACUTE MYELOID LEUKEMIA

Sborník

Background.Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease that accounts for 15% to 20% of childhood leukemia. Over the past decades, the prognosis for children with AML has improved considerably as a result of better (risk-adapted) therapeutic strategies. Risk-group classification has mainly been based on cytogenetic aberrations and response to induction chemotherapy. More recently, novel genetic defects and expression patterns have been discovered that enable the further refinement of risk-category assignment for individual patients. Aims. The transcription factor GATA binding protein-2 (GATA2) gene, located at chromosome 3q21, plays an essential role in the regulation of myeloid lineage determination. In the current study we investigated the relevance and prognostic value of GATA2 expression and mutations in pediatric AML. Methods. In a large cohort of de novo pediatric AML patients, mutation screening of GATA2 was performed using Sanger sequencing. GATA2 expression was determined using gene expression profiling (Affymetrix HGU133 Plus 2.0 microarray) and quantitative real-time PCR. Informed consent was obtained after Institutional Review Board approval according to local laws and regulations, and in accordance with the Declaration of Helsinki.ResultsGATA2 mutations were detected in 5/230 pediatric AML cases, representing a frequency of 2.2% overall, and 9.8% in cytogenetically normal (CN-)AML. Co-occurrence of GATA2 mutations with various other recurrent mutations was observed in all cases (N-RAS mutations (N=4), NPM1 mutations (N=2), CEBPA double mutations (N=2), and WT1 mutations (N=1)). The clinical significance of GATA2 mutations should be determined in a larger cohort. Both at diagnosis and clinical relapse, GATA2 expression was heterogeneous. In 151 out of 237 patients (64%), GATA2 expression at diagnosis was higher than in normal bone marrow. In a subgroup of 38 patients, GATA2 expression was studied during follow-up. In complete remission, normalization of GATA2 expression was observed, whereas GATA2 expression levels stayed high in patients with refractory disease.Importantly, high GATA2 expression at diagnosis proved to be an independent poor prognostic factor for event free survival (HR 2.1, p=0.001) and disease free survival (HR 2.2, p=0.005), with a trend towards worse overall survival (HR 1.7, p=0.056). The prognostic impact of GATA2 was particularly high in specific morphologic and genetic AML-subgroups. High GATA2 expression identified a group of patients with a significantly worse outcome among patients with high WT1 expression. Moreover, in patients with FAB-M5 morphology and inv(16), pronounced differences in survival were observed between patients with high vs. normal GATA2 expression. Summary and Conclusions.  We conclude that high GATA2 expression is a novel poor prognostic marker in pediatric AML, which identifies patients with a severely dismal prognosis in specific AML subgroups. Since GATA2 was a potent poor prognostic factor for overall survival, event free survival and disease free survival, GATA2 expression may be a useful marker for better riskgroup stratification and risk adapted therapy in the future.

Haematologica, 2012; 97(s1):  22