Abstract
In Hodgkin lymphoma (HL) we recently identified deregulated expression of homeobox genes MSX1 and OTX2 which are physiologically involved in development of the embryonal neural plate border region. Here, we examined in HL homeobox gene SIX1 an additional regulator of this embryonal region mediating differentiation of placodal precursors. SIX1 was aberrantly activated in 12 % of HL patient samples in silico, indicating a pathological role in a subset of this B-cell malignancy. In addition, SIX1 expression was detected in HL cell lines which were used as models to reveal upstream factors and target genes of this basic developmental regulator. We detected increased copy numbers of the SIX1 locus at chromosome 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 and transcription factor MEF2C regulate SIX1 expression. Genes encoding the transcription factors GATA2, GATA3, MSX1 and SPIB - all basic lymphoid regulators - were identified as targets of SIX1 in HL. In addition, cofactors EYA1 and TLE4, respectively, contrastingly mediated activation and suppression of SIX1 target gene expression. Thus, the protein domain interfaces may represent therapeutic targets in SIX1-positive HL subsets. Collectively, our data reveal a gene regulatory network with SIX1 centrally deregulating lymphoid differentiation and support concordance of lymphopoiesis/lymphomagenesis and developmental processes in the neural plate border region.
Keywords:
GRN; NKL; cooption; kernel; neural crest.
MeSH terms
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Blotting, Western
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Cell Line, Tumor
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Chromosomes, Human, Pair 14 / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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GATA2 Transcription Factor / genetics
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GATA2 Transcription Factor / metabolism
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Gene Expression Profiling / methods*
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Gene Expression Regulation, Neoplastic*
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Gene Regulatory Networks
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HL-60 Cells
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Hodgkin Disease / genetics
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Hodgkin Disease / metabolism
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Hodgkin Disease / pathology
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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In Situ Hybridization, Fluorescence
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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MEF2 Transcription Factors / genetics
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MEF2 Transcription Factors / metabolism
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MSX1 Transcription Factor / genetics
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MSX1 Transcription Factor / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism
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RNA Interference
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptome / genetics*
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Wnt Signaling Pathway / genetics
Substances
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DNA-Binding Proteins
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GATA2 Transcription Factor
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GATA2 protein, human
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GATA3 Transcription Factor
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GATA3 protein, human
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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MEF2 Transcription Factors
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MSX1 Transcription Factor
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MSX1 protein, human
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Nuclear Proteins
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Repressor Proteins
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SIX1 protein, human
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TLE4 protein, human
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Transcription Factors
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SPIB protein, human
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EYA1 protein, human
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Protein Tyrosine Phosphatases