title: Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications.
abstract: Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies.
authors: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
authors: Stefan
authors: S
authors: Nagel
authors: Stefan
authors: S
authors: Ehrentraut
authors: Jürgen
authors: J
authors: Tomasch
authors: Hilmar
authors: H
authors: Quentmeier
authors: Corinna
authors: C
authors: Meyer
authors: Maren
authors: M
authors: Kaufmann
authors: Hans G
authors: HG
authors: Drexler
authors: Roderick A F
authors: RA
authors: MacLeod
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C405694:Hairy, HRT1 protein
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