Aberrant expression of homeobox gene SIX1 in Hodgkin lymphoma.

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

doi:10.18632/oncotarget.5556

Stefan Nagel, Maren Kaufmann + Show 3 more

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https://doi.org/10.18632/oncotarget.5556

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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.

Highlights

Homeobox genes encode transcription factors (TFs) which regulate basic developmental processes during embryogenesis and in the adult
The homeobox genes MSX1 and OTX2 are involved in the development of the neural plate border region and deregulated in Hodgkin lymphoma (HL) [7, 18,19,20]
The deregulated homeobox gene SIX1 is located at a central position, activated by copy number gains at chromosome 14q23 and by the WNT-signalling pathway, but inhibited www.impactjournals.com/oncotarget by the TF MEF2C

Summary

Introduction

Homeobox genes encode transcription factors (TFs) which regulate basic developmental processes during embryogenesis and in the adult They share the conserved homeodomain which performs binding to both DNA and protein cofactors and serves to divide these genes into classes and subclasses [1]. NKL subclass homeobox gene MSX1 is aberrantly activated in acute T-cell leukemia, mantle cell lymphoma, and Hodgkin lymphoma (HL) [5,6,7]. This gene is physiologically expressed in early lymphopoiesis and undergoes silencing upon differentiation [7, 8]. Additional homeobox genes physiologically involved in lymphopoiesis and in lymphoid malignancies if mutated or deregulated include PAX5 and ZHX2 [7, 10, 11]

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