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.
Highlights
Lymphocytes originate from hematopoietic stem cells located in the bone marrow
We screened by expression profiling 20 leukemia/ lymphoma T- and B-cell lines for aberrant activities of NKLfamily homeobox genes which are implicated in T-cell leukemia [11]
While NKX3-1 was expressed in Hodgkin lymphoma (HL), multiple myeloma (MM), B-cell lymphoma (BCL) and additional diffuse large B-cell lymphoma (DLBCL) cell lines, NKX2-1 was nearly undetectable in the same set of 25 lymphoma cell lines (Fig. 1A), prompting analysis of NKX2-1 and NKX3-1 in primary cells, including thyroid, lung and particular hematopoietic samples to chart physiological tissue specificity in the blood system
Summary
Lymphocytes originate from hematopoietic stem cells located in the bone marrow. While T-cells complete their development in the thymus, B-cells differentiate in various lymphoid tissues. Lymphoid malignancies emerge in the bone marrow or in secondary hematopoietic organs, acquiring both general and subtype specific mutations including chromosomal rearrangements. Subtypes of the diffuse large B-cell lymphoma (DLBCL) differ in mutations and gene activities [1]. The sub-classification of this type of hematopoietic cancer represents a milestone in oncological research and has extensive implications for diagnosis and therapy. Namely germinal center-derived B-cell and activated B-cell, are distinguished within the DLBCL entity [2]. It is believed that additional stratification should contribute to improved and better targeted therapies. Identification of novel genes or gene networks with diagnostic or therapeutic potential is of clinical interest
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