Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies

TY - JOUR

T1 - Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies

AU - Syed, Nelofer

AU - Smith, Paul

AU - Sullivan, Alexandra

AU - Spender, Lindsay C

AU - Dyer, Martin

AU - Karran, Lorraine

AU - O'Nions, Jenny

AU - Allday, Martin

AU - Hoffmann, Ingrid

AU - Crawford, Dorothy

AU - Griffin, Beverley

AU - Farrell, Paul J

AU - Crook, Tim

PY - 2006/1/1

Y1 - 2006/1/1

N2 - The Polo-like kinases (Plks) are a highly conserved family of protein kinases that function in regulation of cell cycle and DNA damage-induced checkpoints. Evidence of a tumor suppressor function for the Plks in human neoplasia is lacking. Here, we report that Snk/Plk2 is transcriptionally down-regulated in B-cell neoplasms. Silencing occurs with very high frequency in Burkitt lymphoma (BL) but is also detected in B-cell neoplasms of other types and is associated with aberrant cytosine methylation in the CpG island located at the 5' end of the SNK/PLK2 gene. Silencing is specific to malignant B cells because SNK/PLK2 was unmethylated (and expressed) in primary B lymphocytes, in EBV-immortalized B lymphoblastoid cell lines (LCLs), and in adenocarcinomas (of the breast) and squamous-cell carcinomas (of the head and neck). Expression of Snk/Plk2 in BL cell lines was restored by demethylating agents. The related PLK1 and PLK3 (FNK/PRK) genes were overexpressed in BL cell lines lacking Snk/Plk2 expression, consistent with functional degeneracy among the Plk family. Ectopic expression of Snk/Plk2 in BL cells resulted in apoptosis, a potential mechanistic basis underlying the strong selective pressure for abrogation of Snk/Plk2 function in B-cell neoplasia.

AB - The Polo-like kinases (Plks) are a highly conserved family of protein kinases that function in regulation of cell cycle and DNA damage-induced checkpoints. Evidence of a tumor suppressor function for the Plks in human neoplasia is lacking. Here, we report that Snk/Plk2 is transcriptionally down-regulated in B-cell neoplasms. Silencing occurs with very high frequency in Burkitt lymphoma (BL) but is also detected in B-cell neoplasms of other types and is associated with aberrant cytosine methylation in the CpG island located at the 5' end of the SNK/PLK2 gene. Silencing is specific to malignant B cells because SNK/PLK2 was unmethylated (and expressed) in primary B lymphocytes, in EBV-immortalized B lymphoblastoid cell lines (LCLs), and in adenocarcinomas (of the breast) and squamous-cell carcinomas (of the head and neck). Expression of Snk/Plk2 in BL cell lines was restored by demethylating agents. The related PLK1 and PLK3 (FNK/PRK) genes were overexpressed in BL cell lines lacking Snk/Plk2 expression, consistent with functional degeneracy among the Plk family. Ectopic expression of Snk/Plk2 in BL cells resulted in apoptosis, a potential mechanistic basis underlying the strong selective pressure for abrogation of Snk/Plk2 function in B-cell neoplasia.

KW - Apoptosis

KW - B-Lymphocytes

KW - Cell Cycle Proteins

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Gene Silencing

KW - Humans

KW - Leukemia, B-Cell

KW - Lymphoma, B-Cell

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins

KW - Transcription, Genetic

KW - Tumor Cells, Cultured

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1182/blood-2005-03-1194

DO - 10.1182/blood-2005-03-1194

M3 - Article

C2 - 16160013

SN - 0006-4971

VL - 107

SP - 250

EP - 256

JO - Blood

JF - Blood

IS - 1

ER -