Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALLReport as inadecuate




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Journal of Hematology and Oncology

, 9:95

First Online: 22 September 2016Received: 14 April 2016Accepted: 09 September 2016DOI: 10.1186-s13045-016-0324-8

Cite this article as: Fransecky, L., Neumann, M., Heesch, S. et al. J Hematol Oncol 2016 9: 95. doi:10.1186-s13045-016-0324-8

Abstract

BackgroundGATA3 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.

MethodsWe 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 and GATA3 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.

ResultsIn our cohort of 70 ETP-ALL patients, 33 % 23-70 lacked GATA3 expression and were thus defined as GATA3. DNA methylation analysis revealed a high degree of GATA3 CpG island methylation in GATA3 compared with GATA3 ETP-ALL patients mean 46 vs. 21 %, p < 0.0001. Genome-wide expression profiling of GATA3 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 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.

ConclusionsWe propose GATA3 ETP-ALL as a novel stem cell-like leukemia with implications for the use of myeloid-derived therapies.

KeywordsGATA3 ETP-ALL PER-117 Decitabine Electronic supplementary materialThe online version of this article doi:10.1186-s13045-016-0324-8 contains supplementary material, which is available to authorized users.

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Author: L. Fransecky - M. Neumann - S. Heesch - C. Schlee - J. Ortiz-Tanchez - S. Heller - M. Mossner - S. Schwartz - L. H. Moch

Source: https://link.springer.com/







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