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

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

doi:10.18632/oncotarget.26459

Stefan Nagel, Hans G Drexler + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.26459

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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.

Highlights

Hodgkin lymphoma (HL) is a B-cell malignancy comprising some 10% of all lymphomas
At the same time the genes DAZAP2 and SMURF2 were deregulated via genomic aberrations and supported NKX2-2 expression probably via co-activation of IL17RB [35]
Downstream of IL17RB we identified the transcription factors www.oncotarget.com (TFs) FOXG1 and FLI1 which in turn activate NKX2-2 transcription

Summary

Introduction

Hodgkin lymphoma (HL) is a B-cell malignancy comprising some 10% of all lymphomas. This cancer is subclassified into two distinct entities according to clinical and histopathological features, namely classical HL (cHL) and nodular lymphocyte predominant (NLP) HL [1]. Sternberg (HRS) cells, infiltrate lymph nodes where they are vastly outnumbered by predominant bystander cells which include activated lymphocytes, plasma cells and granulocytes [2]. This picture reflects aberrant expression of several signalling molecules by HRS cells, notably interleukins and other growth factors together with their receptors which mediate constitutive activation of the associated signalling pathways and transcription factors www.oncotarget.com (TFs) [3]. While most available HL cell lines belong to the cHL group DEV represents the NLPHL entity [5, 6]. This discrimination is supported by recent cluster analyses using expression profiling data from all bona fide HL cell lines [7]

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