Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B.
Deletion of 11q22-q23 is associated with an aggressive course of B-cell chronic lymphocytic leukaemia (B-CLL). Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NPAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction. Though none of the genes were affected by deleterious mutations, we observed a significant down-regulation of NPAT in B-CLL versus CD19+ B cells and of CUL5 in 11q deletion versus non-deletion B-CLL samples and measured reduced PPP2R1B transcript levels in a subset of B-CLL cases. Alternative splicing of PPP2R1B transcripts (skipping of exons 2/3, 3, 9) was associated with a reduced activity of protein phosphatase 2A. Together, these results implicate deregulation of the cell-cycle and apoptosis regulators NPAT, CUL5 and PPP2R1B and a role for these genes in the pathogenesis of B-CLL.
Kalla
Claudia
C
Division of Molecular Genetics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. c.schaffner@dkfz.de
Scheuermann
Markus O
MO
Kube
Ina
I
Schlotter
Magdalena
M
Mertens
Daniel
D
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
Lichter
Peter
P
D001483:Base Sequence / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D054648:Protein Phosphatase 2; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
C496871:CUL5 protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C101693:NPAT protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C432785:PPP2R1B protein, human; D054648:Protein Phosphatase 2