Haema 2013; 4(2):135-143
by Nikos Papakonstantinou1,2, Chrissoula Mpelessi3
1Department of Molecular Biology and Genetics, Democritus University of Thake, Alexandroupolis,
2Institute of Applied Biosciences, National Centre of Research and Technological Development, Thessaloniki,
3Hematological Department, General Hospital of Nikaia, Greece
Abstract
Chronic Lympocytic Leukemia (CLL) is the most frequent adult leukemia in the West. It is characterized by the in vivo accumulation of monoclonal B cell lymphocytes in the blood, bone marrow, lymphoid tissues and spleen. There is a great heterogeneity in the clinical outcome of CLL with a proportion of patients following an aggressive course with short survival, contrasting others who experience a relatively indolent disease with no need for treatment and finally die due to other reasons. The high degree of clinical heterogeneity between individual patients combined with the fact that the systems used for clinical staging of the disease lack predictive value in early stage patients, have prompted research for identifying new biological markers with prognostic value. Recent studies have shown that clinical heterogeneity is related with heterogeneity observed at the biological level and new immunophenotypic, cytogenetic and molecular markers have been found to show higher accuracy in the prediction of the final outcome. Εxamples of biomarkers in CLL are the CD38 and ZAP-70 immunophenotypic markers, whose expression is associated with bad prognosis. Additionally, genomic aberrations have also been correlated with prognosis. The chromosome 13q deletion is considered to be a marker of a relatively indolent disease, while the deletion of chromosomes 11q22-23 and, especially, 17p13 have been correlated with resistance to chemotherapy and poor outcome. The analysis of B-cell receptor (BcR) molecular features had a great impact on prognostication, and also revealed the critical role of the interaction of CLL cells with their microenvironment, mainly through their BcR. This analysis revealed two categories of CLL, with or without somatic mutations in their BcRs: cases belonging to the first category have more indolent disease with longer overall survival, while cases belonging to the latter category have more aggressive disease. Additionally, subsets of patients with nearly identical or very similar BcRs (stereotyped receptors) were identified in approximately 30% of cases of CLL. Cases belonging to stereotyped subsets recognize similar antigens, share similar clinical characteristics and exhibit distinct prognosis. Finally, recent studies in the field of epigenetics confirmed the heterogeneity of the disease, reporting distinct microRNA expression and DNA methylation profiles in distinct subgroups of CLL patients with different prognosis and outcome, linked to dysregulation of a plethora of genes involved in cancer. In conclusion, studies of the last 20 years have contributed significantly to the understanding of the pathogenesis of CLL and showed that, regardless of the heterogeneity at the immunophenotypic, cytogenetic or molecular level, all CLL cells are antigen-experienced. However, it is still unclear which is the normal counterpart of CLL cells, whether a single or multiple normal precursors were stimulated to evolve into CLL, at what stage(s) this occurred and which are the implicated antigens.