Oncotarget

Research Papers:

NKL homeobox gene NKX2-2 is aberrantly expressed in Hodgkin lymphoma

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

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Oncotarget. 2018; 9:37480-37496. https://doi.org/10.18632/oncotarget.26459

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Abstract

Stefan Nagel1, Roderick A.F. MacLeod1, Claudia Pommerenke1, Corinna Meyer1, Maren Kaufmann1 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; Hodgkin lymphoma

Received: October 11, 2018    Accepted: November 29, 2018    Published: December 25, 2018

ABSTRACT

NKL homeobox genes encode basic transcriptional regulators of cell and tissue differentiation. Recently, we described a hematopoietic NKL-code comprising nine specific NKL homeobox genes expressed in normal hematopoietic stem cells, lymphoid progenitors and during lymphopoiesis, highlighting their physiological role in the development of T-, B- and NK-cells. Here, we identified aberrant expression of the non-hematopoietic neural NKL homeobox gene NKX2-2 in about 12% of both, classical Hodgkin lymphoma (HL) and nodular lymphocyte predominant (NLP) HL patients. The NKX2-2 expressing NLPHL-derived cell line DEV served as a model by analysing chromosomal configurations and expression profiling data to reveal activating mechanisms and downstream targets of this developmental regulator. While excluding chromosomal rearrangements at the locus of NKX2-2 we identified t(3;14)(p21;q32) resulting in overexpression of the IL17 receptor gene IL17RB via juxtaposition with the IGH-locus. SiRNA-mediated knockdown experiments demonstrated that IL17RB activated NKX2-2 transcription. Overexpression of IL17RB-cofactor DAZAP2 via chromosomal gain of 12q13 and deletion of its proteasomal inhibitor SMURF2 at 17q24 supported expression of NKX2-2. IL17RB activated transcription factors FLI1 and FOXG1 which in turn mediated NKX2-2 expression. In addition, overexpressed chromatin-modulator AUTS2 contributed to NKX2-2 activation as well. Downstream analyses indicated that NKX2-2 inhibits transcription of lymphoid NKL homeobox gene MSX1 and activates expression of basic helix-loop-helix factor NEUROD1 which may disturb B-cell differentiation processes via reported interaction with TCF3/E2A. Taken together, our data reveal ectopic activation of a neural gene network in HL placing NKX2-2 at its hub, highlighting a novel oncogenic impact of NKL homeobox genes in B-cell malignancies.


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