Protein expression analysis of chronic lymphocytic leukemia defines the effect of genetic aberrations and uncovers a correlation of CDK4, P27 and P53 with hierarchical risk.
BACKGROUND
Chronic lymphocytic leukemia has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms that are poorly understood. In particular it remains unclear whether the prognostic subgroups of chronic lymphocytic leukemia are characterized by different levels of leukemogenic proteins.


METHODS
Expression of 23 proteins involved in apoptosis, proliferation, DNA damage, and signaling or whose genes map to chromosomal regions known to be critical in chronic lymphocytic leukemia was quantified in 185 cytogenetically well characterized cases of chronic lymphocytic leukemia using immunoblotting. Cases were categorized hierarchically into deletion(17p), deletion(11q), trisomy 12, deletion(13q) as sole abnormality or normal karyotype. Statistical analysis was performed for expression differences between these subgroups. In addition, the expression levels of CDK4, P27 and P53 were quantified over the clinical course and compared to levels in immunopurified B cells from healthy individuals.


RESULTS
In subgroups with a good prognosis, differential expression was mainly seen for proteins that regulate apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, differential expression was mostly detected for proteins that control DNA damage and proliferation. Expression levels of CDK4, P27 and P53 were higher compared to those in B cells from healthy individuals and significantly correlated with increasing hierarchical risk. In addition, no significant longitudinal changes of expression levels of CDK4, P27 and P53 could be detected in chronic lymphocytic leukemia patients.


CONCLUSIONS
Differences in expression levels of apoptosis- and proliferation-controlling proteins define distinct prognostic subgroups of chronic lymphocytic leukemia and uncover a correlation of levels of CDK4, P27 and P53 proteins with higher hierarchical risk.
Winkler
Dirk
D
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
Schneider
Christof
C
Zucknick
Manuela
M
Bögelein
Daniela
D
Schulze
Kerstin
K
Zenz
Thorsten
T
Mohr
Julia
J
Philippen
Angela
A
Huber
Henriette
H
Bühler
Andreas
A
Habermann
Annett
A
Benner
Axel
A
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
Mertens
Daniel
D
D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008297:Male; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4