Unknown,Transcriptomics,Genomics,Proteomics

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Homeobox protein NKX2-3 modulates lymphocyte dynamics and promotes B-cell lymphomagenesis

ABSTRACT: Molecular cloning of a t(10;14)(q24;q32) from a B-cell lymphoma showed a recurrent breakpoint in homeobox NKX2-3 gene, which was highly expressed in comparison to non-expressing mature B lymphocytes. Epigenetically-mediated NKX2-3 over-expression was selectively found in patients with splenic marginal-zone lymphoma, MALT lymphoma and extranodal diffuse large-cell lymphoma. In young mice, restricted expression of NKX2-3 to lymphocytes activated multiple integrins (LFA-1, VLA-4, MAC-1), adhesion molecules (ICAM-1, MadCAM-1, L-selectin) and the chemokine receptor CXCR4 that enhanced their homing and migration to splenic tissues, whereby they were retained, progressively accumulating to form non-clonal tumors. At 18 months, B cells acquired genomic rearrangements and generated clonal B-cell lymphomas mirroring the spectrum of human NKX2-3-expressing tumors. Mouse and human lymphomas displaying NKX2-3 expression shared histopahological, genomic and molecular features, including canonical NF-KB activation. NF-KB inhibition reduced tumorigenecity of NKX2-3-positive lymphomas. Our study reveals that oncogenic NKX2-3 promotes B-cell lymphomagenesis by disturbing lymphocyte dynamics. Comparisson of global gene expression profiling between Emu-NKX2-3 transgenes mice and wild type mice.

ORGANISM(S): Mus musculus

SUBMITTER: Victor Segura

PROVIDER: E-GEOD-49356 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Abstract. Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematological malignancies enhanced NF-kB exerts prosurvival functions. Here we investigated the role of NF-kB in mouse and human c-MYC-transformed lymphomas. The NF-kB-pathway is extinguished in murine lymphoma cells and extrinsic stimuli typically inducing NF-kB activity fail to activate this pathway. Genetic activation of the NF-kB pathway induces apoptosis in these cells, while inhibition of NF-kB by an IkBa superrepressor provides a selective advantage in vivo. Furthermore, in human BurkittÂ´s lymphoma cells we find that NF-kB activation induces apoptosis. NF-kB upregulates Fas and predisposes to Fas-induced cell death, which is caspase 8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-kB-induced apoptosis and persistent inacvtivity of NF-kB signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC driven lymphoma cells is reversed by activation of NF-kB. Our observations provide a molecular explanation for the described absence of the NF-kB signaling in BurkittÂ´s lymphoma and question the applicability of NF-kB inhibitors as candidates for treatment of this cancer. Experiment Overall Design: Ramos cells were transfected in triplicates with pRTS-GFP (A+,C+,D+) or pRTS-CA-IKK2 (E+,F+,H+), selected with hygromycin and transgene expression was induced with doxycycline (0,5mg/ml) for 48hrs. RNA was isolated with RNeasy mini kit (Qiagen, Venlo, Netherlands) and Gene expression profiling (GEP) was performed using Affymetrix Human Genome U133 Plus 2.0 Array (Affymetrix, Santa Clara, CA, USA). 2 Âµg of total RNA were labeled using the GeneChipÂ® One-Cycle Target Labeling assay kit (Affymetrix). After hybridization arrays were stained and washed in a FS 450 Fluidics station (Affymetrix) before imaging on an Affymetrix GeneChip (3000) scanner. Raw data were generated using the GCOS 1.4 software (Affymetrix). Probe level data were obtained using the Robust Multichip Average (RMA) normalization algorithm and CEL files were loaded into Genesifter (GeneSifter.Net, VizX Laboratories, Seattle, WA, USA). Genes were identified as differentially expressed among the two classes if a two-sample T-test revealed a nominal significance level of 0.05 and the ratio between the two classes was at least 2 fold. Calculation of false discovery rate was done according to the method of Benjamini and Hochberg. Biological significance was determined using Gene Ontolgy reports.

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Homeobox protein NKX2-3 modulates lymphocyte dynamics and promotes B-cell lymphomagenesis

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