Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL.

ABSTRACT: GATA3 is pivotal for the development of T lymphocytes. While its effects in later stages of T cell differentiation are well recognized, the role of GATA3 in the generation of early T cell precursors (ETP) has only recently been explored. As aberrant GATA3 mRNA expression has been linked to cancerogenesis, we investigated the role of GATA3 in early T cell precursor acute lymphoblastic leukemia (ETP-ALL).We analyzed GATA3 mRNA expression by RT-PCR (n?=?182) in adult patients with T-ALL. Of these, we identified 70 of 182 patients with ETP-ALL by immunophenotyping. DNA methylation was assessed genome wide (Illumina Infinium® HumanMethylation450 BeadChip platform) in 12 patients and GATA3-specifically by pyrosequencing in 70 patients with ETP-ALL. The mutational landscape of ETP-ALL with respect to GATA3 expression was investigated in 18 patients and validated by Sanger sequencing in 65 patients with ETP-ALL. Gene expression profiles (Affymetrix Human genome U133 Plus 2.0) of an independent cohort of adult T-ALL (n?=?83) were used to identify ETP-ALL and investigate GATA3(low) and GATA3(high) expressing T-ALL patients. In addition, the ETP-ALL cell line PER-117 was investigated for cytotoxicity, apoptosis, GATA3 mRNA expression, DNA methylation, and global gene expression before and after treatment with decitabine.In our cohort of 70 ETP-ALL patients, 33 % (23/70) lacked GATA3 expression and were thus defined as GATA3(low). DNA methylation analysis revealed a high degree of GATA3 CpG island methylation in GATA3(low) compared with GATA3(high) ETP-ALL patients (mean 46 vs. 21 %, p?

SUBMITTER: Fransecky L 

PROVIDER: S-EPMC5034449 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature