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

Fransecky, L.; Neumann, M.; Heesch, S.; Schlee, C.; Ortiz-Tanchez, J.; Heller, S.; Mossner, M.; Schwartz, S.; Mochmann, L. H.; Isaakidis, K.; Bastian, L.; Kees, U. R.; Herold, T.; Spiekermann, K.; Gökbuget, N. und Baldus, C. D. (2016): Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL. In: Journal of Hematology & Oncology 9:95

Abstract

Background: 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). Methods: 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((R)) 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. Results: 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 < 0.0001). Genome-wide expression profiling of GATA3(low) ETP- ALL exhibited enrichment of myeloid/lymphoid progenitor (MLP) and granulocyte/monocyte progenitor (GMP) genes, while T cell-specific signatures were downregulated compared to GATA3(high) ETP-ALL. Among others, FLT3 expression was upregulated and mutational analyses demonstrated a high rate (79%) of FLT3 mutations. Hypomethylating agents induced reversal of GATA3 silencing, and gene expression profiling revealed downregulation of hematopoietic stem cell genes and upregulation of T cell differentiation. Conclusions: We propose GATA3(low) ETP-ALL as a novel stem cell-like leukemia with implications for the use of myeloid-derived therapies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1756-8722
• Sprache: Englisch