Clinical and prognostic importance of GATA2 domains in patients with acute myeloid leukemia

Mutations in the GATA binding protein 2 (GATA2), a transcription factor, have been reported in 3.6% of patients with French- American-British (FAB) M5 subtype of acute myeloid leukemia (AML). Somatic mutations in the GATA2 usually cluster in two zinc finger (ZF) domains. However, the impact of mutations in different domains of GATA2 on the clinico-biological features and outcomes in patients with AML is not yet elucidated.

Taiwanese researchers from the National Taiwan University Hospital (NUTH) investigated the clinical and prognostic impact of mutations in the different GATA2 domains in patients with non-M3 AML. The dynamic changes of mutations were also analyzed. The results of the study were published in Blood Cancer Journal.

Six hundred and ninety-three newly diagnosed patients with non-M3 AML who were enrolled between 1994–2011 at the NUTH were analyzed in this study.

Key findings:

• Forty-four distinct GATA2 mutations were identified in 6.2% (43/693) of patients
  • Thirty-one mutations were clustered in the highly conserved N-terminal ZF domain (ZF1 domain)
  • Ten mutations clustered within the C-terminal ZF domain (ZF2 domains)
  • Three mutations were scattered outside the ZF domains
• ZF1-mutated AML patients had a higher incidence of FAB M1 subtype than ZF2-mutated patients, P = 0.044
• Compared to ZF2-mutated patients and wild-type patients, only ZF1-mutated patients had a significantly higher frequency of CEBPA double mutations
• ZF1-mutated patients had a lower frequency of NPM1, FLT3-ITD and a lower incidence of FAB M4 subtype

Clinical outcomes of 469 AML patients including 27 GATA2 ZF1-mutated and nine GATA ZF2-mutated patients who underwent conventional intensive chemotherapy was evaluated.

• Complete remission (CR) rate: 75.1% (352/469)
  • CR rate in ZF1-mutated patients: 85.2%
  • CR rate in ZF2-mutated patients: 60%
• Median follow-up = 78.6 months (range, 0.1–236)
• Patients with GATA2 mutations had a trend for a longer overall survival (OS) and disease-free survival (DFS) than wild-type patients
• 5-year OS in patients with ZF1- and GATA2-wild-type patients: 72% vs 43%, P = 0.003
• Median DFS in patients with ZF1- and GATA2-wild-type patients: 91.2 vs8 months, P = 0.022
• ZF2 mutations had a similar OS and DFS with GATA-wild type patients
• ZF1 mutations associated with a better OS than ZF2 mutations, P = 0.001
• In patients with CEBPA double mutations, ZF1 mutation predicted for a longer OS and DFS

Sequential studies were performed in 419 samples from 124 patients (19 patients with and 105 patients without GATA2 mutations) who obtained CR in order to evaluate dynamic changes in mutations

• Among the 19 GATA2 mutated patients, original GATA2 mutations were lost at remission
• Five of the six patients in relapse regained GATA2 mutation at relapse

In summation, this is the first study to investigate the differences in clinical and biological implications between the GATA2 ZF1 and ZF2 mutations in a large cohort of patients with AML.  

The researchers concluded by stating that “GATA2 ZF1 mutations are associated with distinct clinico-biological features and predict better prognosis, different from ZF2 mutations, in AML patients.” They further added that “incorporation of GATA2 ZF1, not ZF2 mutations, allows further refinement of the WHO classification in the specific entity of AML with CEBPA double mutations.”