Chronic Lymphocytic Leukemia (CLL) with a High Number of Losses in 13q Is Associated with Different Biological Features
Ana E Rodriguez, Jose-Angel Hernandez, Maria Hernandez, Rocio Benito, Cristina Robledo, Eva Lumbreras, Maria Abaigar, Monica del Rey, Maribel Forero, Alberto Risueno, Encarna Ferminan, Juan-Luis Garcia, Norma C Gutierrez, Javier de las Rivas, Jesus-Maria Hernandez. Comprehensive Cancer Center Research-USAL, Salamanca, Spain; Hospital Universitario Infanta Leonor, Madrid, Spain; IECSCYL, Salamanca, Spain; Hospital Clínico Universitario, Salamanca, Spain
Background: 13q deletion (13q-) is the most common cytogenetic aberration in CLL and is usually associated with a favorable prognosis as the sole abnormality. However, recent data have shown that CLL patients carrying higher percentages of 13q- cells have more aggressive clinical courses. However the molecular characteristics of these patients have not been so far analyzed in detail.
Design: A total of 97 CLL samples and 5 healthy donors (HD) were analyzed. For the gene expression profile (GEP) analysis two groups of 13q- patients were compared: CLL with >80% (13q-H) and <80% (13q-L) of 13q- cells. All samples were hybridized with the Affymetrix Human Exon array 1.0ST. Gene-specific qPCR and quantification of miRNA expression level were carried out in selected patients.
Results: CLL patients with a high number of 13q- cells can be differentiated based on their expression profile. Thus a total of 3450 genes significantly distinguished 13q-H from 13q-L patients and define the 13q-H signature. This deregulation affected genes involved in apoptosis, BCR and NF-kB signaling, leading to increased proliferation and decreased apoptosis in 13q-H cases. Moreover, 13q-H patients were also characterized by a striking overrepresentation of deregulated miRNAs. Thus 15 miRNAs were deregulated, being miR155 the most upregulated miRNA and miR223 the most significantly downregulated. The analysis of the post-transcriptional regulatory network of miRNA and genes in 13q-H patients revealed that BCR, PI3K and NFkB signaling were among the most strongly affected pathways and highlights the importance of miRNA regulation in CLL. Morevoer the gene signature of 13q- CLL patients in comparison with HD and other CLL cytogenetic subgroups was analyzed. As expected, the expression pattern of Bcells from CLL patients was notably different from the GEP of Bcells from HD. Surprisingly, our results suggested that the gene expression pattern of 13q-H could be similar to that of high-risk cytogenetic subgroups while the GEP of B lymphocytes from 13q-L and normal FISH subgroups was similar.
Conclusions: Our study provides new insights in the biological mechanisms underlying the clinical differences observed in CLL with 13q-.
Monday, March 4, 2013 8:00 AM
Proffered Papers: Section C, Monday Morning