Oncotarget

Research Papers:

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

Stefan Nagel _, Claudia Pommerenke, Corinna Meyer, Maren Kaufmann, Hans G. Drexler and Roderick A.F. MacLeod

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:45398-45413. https://doi.org/10.18632/oncotarget.9982

Metrics: PDF 1388 views  |   HTML 1596 views  |   ?  


Abstract

Stefan Nagel1, Claudia Pommerenke1, Corinna Meyer1, Maren Kaufmann1, Hans G. Drexler1, Roderick A.F. MacLeod1

1Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

Correspondence to:

Stefan Nagel, email: sna@dsmz.de

Keywords: IL-7, IL7R, MEF2C, PRC1, PRC2

Received: March 02, 2016     Accepted: May 29, 2016     Published: June 13, 2016

ABSTRACT

Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages. AUTS2 expression was higher in normal B-cells than in T-cells, indicating lineage-specific activity in lymphopoiesis. While excluding chromosomal aberrations, examinations of AUTS2 transcriptional regulation in T-ALL cells revealed activation by IL7-IL7R-STAT5-signalling and MEF2C. AUTS2 protein has been shown to interact with polycomb repressor complex 1 subtype 5 (PRC1.5), transforming this particular complex into an activator. Accordingly, expression profiling and functional analyses demonstrated that AUTS2 activated while PCGF5 repressed transcription of NKL homeobox gene MSX1 in T-ALL cells. Forced expression and pharmacological inhibition of EZH2 in addition to H3K27me3 analysis indicated that PRC2 repressed MSX1 as well. Taken together, we found that AUTS2 and MEF2C, despite lying on different chromosomes, share strikingly similar regulatory upstream regions and aberrant expression in T-ALL subsets. Our data implicate chromatin complexes PRC1/AUTS2 and PRC2 in a gene network in T-ALL regulating early lymphoid differentiation.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 9982