Aberrant Expression of Homeobox Gene SIX1 in Hodgkin Lymphoma

In Hodgkin lymphoma (HL) we recently identified deregulated expression of homeobox gene MSX1 which physiologically controls development of the embryonal neural plate border region. This region forms the neural crest and placodes which in turn give rise to fundamental structures and functions of the head including jaw and sensory organs. Here, we examined in HL another homeobox gene, SIX1, an additional regulator of this embryonal region mediating differentiation of placodal precursors. In silico data (GSE12453) show aberrantly activated SIX1 in 12 % of HL patient samples, indicating a pathological role in a subset of this malignancy. In addition, SIX1 expression was detected in HL cell lines which then were used as models to reveal regulators and target genes of this basic developmental factor. Cytogenetics and quantitative genomic PCR revealed copy number gains of the SIX1 locus at chromosomal band 14q23 correlating with enhanced expression while chromosomal translocations were absent. Moreover, comparative expression profiling data and pertinent gene modulation experiments indicated that the WNT-signalling pathway activates and transcription factor MEF2C suppresses SIX1 expression. MAPK7/ERK5 and HDAC9 phosphorylate and deacetylate MEF2C, respectively, boosting or constraining its inhibitory capacity. MEF2C, MAPK7 and HDAC9 show aberrant expression levels in both HL cell lines and patient samples, collectively restricting the inhibitory activity of MEF2C. Genes encoding the transcription factors GATA2, GATA3, MSX1 and SPIB – all basic lymphoid regulators - were identified as targets of SIX1 in HL, contributing to deregulated B-cell differentiation in this malignancy. In addition, cofactors EYA1 and TLE4 contrastingly mediated activation and suppression of SIX1 target gene expression, respectively. Thus, the protein domain interfaces may represent therapeutic targets in SIX1-positive HL subsets to prevent cofactor interactions and subsequent target gene regulation. Collectively, our data reveal a gene regulatory network where SIX1 centrally deregulates lymphoid differentiation. Additionally, our data strengthen the emerging concordance of lymphopoiesis/lymphomagenesis and the neural plate border region ontogeny.