The Clinical and Biological Characterization of De Novo Acute Myeloid Leukemia (AML) with GATA2 Mutation
Authors: Tien Feng-Ming , Chou Wen-Chien , Hou Hsin-An , Chiu Yu-Chiao , Chuang Eric Y. , Chen Chien-Yuan , Tang Jih-Luh , Yao Ming , Huang Shang-Yi , Ko Bor-Sheng , Hsu Szu-Chun , Wu Shang-Ju , Tsay Woei , Tien Hwei-Fang 
Published: October 2019

Abstract
Introduction
GATA-binding factor 2 (GATA2) contributes to the regulation of hematopoietic stem cell proliferation and differentiation. Mutations of GATA2 are identified in AML patients, but their clinical and biological correlations in AML remain to be delineated.
Methods and Materials
We determined GATA2 mutations by Sanger sequencing and next generation sequencing in consecutively enrolled 766 newly diagnosed de novo AML patients who had cryopreserved cells for analysis. The expression of GATA2 was also analyzed by microarray in 335 patients. We then looked for the clinical and biological correlations of the expression levels and mutation status of GATA2. Computational network analysis of GATA2 mutations was conducted by Ingenuity Pathway Analysis (IPA) and Gene set enrichment analysis (GSEA).
Result
GATA2 mutations were detected in 58 patients (7.5%) and were associated with FAB M1 subtype, and intermediate-risk cytogenetics, but negatively associated with M4 subtype and favorable-risk cytogenetics. There was no difference in other clinical parameters such as age, hemogram and LDH levels between the patients with and without GATA2 mutations. GATA2 mutations were closely associated with CEBPA double mutations (44.8% vs. 10.2%, P<0.001), but negatively associated with WT1 (0% vs. 7.4%, P=0.003) and IDH1 mutations (0% vs. 6.4%, P<0.0001). The mutation hot spots were between amino acids 315 to 361. The mutant burden ranged from 4.89% to 52% with a median of 35.31%. Only two patients harbored 2 mutations; mutations in the others were heterozygous. Most were point mutations except for 3 (5.5%) with indel.
With a median follow-up time of 25 months (ranges 0 to 160), patients with GATA2 mutations had a trend of better overall survival (OS) than those without GATA2 mutations (median 40.7 vs. 24.9 months P=0.123). Among patients with CEBPA double mutations, there was also a trend toward better OS in patients concomitant with GATA2 mutations (P=0.199).
By comparing the mRNA expression profiles between patients with and without GATA2 mutations, we found GATA2 expression levels were higher in those with GATA2 mutations (P=0.003). GATA2 mutations were also associated with a significant change in genes related to cell proliferation and differentiation by IPA.
We also performed GSEA analysis to identify modest functional changes related to GATA2 mutation status. Leukemogenesis-related genes were significantly enriched in the GATA2-mutated subgroup (nominal P value= 0.006; Normalized enrichment score= 1.62), whereas gene signatures associated with myeloid differentiation, apoptosis, leukemia cell death, CEBPA and WT1 pathways were enriched in GATA2 -wild type patients.
Conclusion
GATA2 mutations, which are commonly heterozygous point mutations between amino acids 315 to 361, occur in 7.5% of AML patients and are associated with certain clinical features, a trend of better treatment outcome, and higher GATA2 expression. The GATA2 mutation-associated expression signatures suggest the effects on leukemogenesis by GATA2 mutations.
Figure 1. Figure 1.

Disclosures
Tang: Novartis: Consultancy, Honoraria.