Oncotarget

Research Papers:

Aberrant expression of NKL homeobox gene HLX in Hodgkin lymphoma

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

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Oncotarget. 2018; 9:14338-14353. https://doi.org/10.18632/oncotarget.24512

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Abstract

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

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: homeobox; NKL-code; T-ALL

Received: October 17, 2017     Accepted: February 10, 2018     Epub: February 16, 2018     Published: March 06, 2018

ABSTRACT

NKL homeobox genes are basic regulators of cell and tissue differentiation, many acting as oncogenes in T-cell leukemia. Recently, we described an hematopoietic NKL-code comprising six particular NKL homeobox genes expressed in hematopoietic stem cells and lymphoid progenitors, unmasking their physiological roles in the development of these cell types. Hodgkin lymphoma (HL) is a B-cell malignancy showing aberrant activity of several developmental genes resulting in disturbed B-cell differentiation. To examine potential concordances in abnormal lymphoid differentiation of T- and B-cell malignancies we analyzed the expression of the hematopoietic NKL-code associated genes in HL, comprising HHEX, HLX, MSX1, NKX2-3, NKX3-1 and NKX6-3. Our approach revealed aberrant HLX activity in 8 % of classical HL patients and additionally in HL cell line L-540. Accordingly, to identify upstream regulators and downstream target genes of HLX we used L-540 cells as a model and performed chromosome and genome analyses, comparative expression profiling and functional assays via knockdown and overexpression experiments therein. These investigations excluded chromosomal rearrangements of the HLX locus at 1q41 and demonstrated that STAT3 operated directly as transcriptional activator of the HLX gene. Moreover, subcellular analyses showed highly enriched STAT3 protein in the nucleus of L-540 cells which underwent cytoplasmic translocation by repressing deacetylation. Finally, HLX inhibited transcription of B-cell differentiation factors MSX1, BCL11A and SPIB and of pro-apoptotic factor BCL2L11/BIM, thereby suppressing Etoposide-induced cell death. Collectively, we propose that aberrantly expressed NKL homeobox gene HLX is part of a pathological gene network in HL, driving deregulated B-cell differentiation and survival.


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