Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes.
OBJECTIVE
In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12q, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence.


METHODS
Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q-, +12, 11q-, and 17p-.


RESULTS
The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q-, and 17p-, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators: AKT (up) in 13q, E2F1 (up) in +12, MYC (up) and BCL-2 (down) in 17p-, and CCND3 (down) in 11q- as well as 17p-. The 17p- subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3K.


CONCLUSIONS
The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.
Kienle
Dirk L
DL
Department of Internal Medicine III, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
Korz
Christian
C
Hosch
Beate
B
Benner
Axel
A
Mertens
Daniel
D
Habermann
Annett
A
Kröber
Alexander
A
Jäger
Ulrich
U
Lichter
Peter
P
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate
D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell