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Open Access 01-12-2016 | Research

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

Authors: L. Fransecky, M. Neumann, S. Heesch, C. Schlee, J. Ortiz-Tanchez, S. Heller, M. Mossner, S. Schwartz, L. H. Mochmann, K. Isaakidis, L. Bastian, U. R. Kees, T. Herold, K. Spiekermann, N. Gökbuget, C. D. Baldus

Published in: Journal of Hematology & Oncology | Issue 1/2016

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® 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.

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Title: Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL
Authors: L. Fransecky
M. Neumann
S. Heesch
C. Schlee
J. Ortiz-Tanchez
S. Heller
M. Mossner
S. Schwartz
L. H. Mochmann
K. Isaakidis
L. Bastian
U. R. Kees
T. Herold
K. Spiekermann
N. Gökbuget
C. D. Baldus
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0324-8

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Abstract

Background

Methods

Results

Conclusions

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