BioProject

NKL homeobox genes encode basic transcriptional regulators of cell and tissue differentiation. More...

NKL homeobox genes encode basic transcriptional regulators of cell and tissue differentiation. Recently, we described a hematopoietic NKL-code comprising particular NKL homeobox genes expressed in normal hematopoietic stem cells and during lymphopoiesis, highlighting their physiological role in the development of T-, B- and NK-cells. Here, we describe aberrant expression of the neural non-hematopoietic NKL homeobox gene NKX2-2 in 10% of both classical Hodgkin lymphoma (HL) and nodular lymphocyte predominant (NLP) HL patients. NKX2-2 expressing NLPHL 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;q34) resulting in overexpression of the IL17 receptor gene IL17RB via juxtaposition to 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. NKX2-2 inhibited transcription of lymphoid NKL homeobox gene MSX1 and activated 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 in HL ectopic activation of a neural gene network showing NKX2-2 at a central position, highlighting oncogenic impacts of NKL homeobox genes in B-cell malignancies. Overall design: Hodgkin lymphoma cell line characterisation. Less...