High rate of centrosome aberrations and correlation with proliferative activity in patients with untreated B‐cell chronic lymphocytic leukemia

Abstract

B‐cell chronic lymphocytic leukemia (CLL) is characterized by a high rate of clonal genomic alterations and a low proliferative activity with cell cycle arrest in G0/G1 phase. Recently, centrosome aberrations have been described as a possible cause of chromosomal instability and aneuploidy in many human malignancies. To investigate whether centrosome aberrations do occur in CLL and whether they correlate with common prognostic factors and disease activity, we examined peripheral blood mononuclear cells (PBMC) from 70 patients with previously untreated CLL using an antibody to γ‐tubulin. All 70 CLL samples displayed significantly more cells with centrosome aberrations (median: 26.0%, range 11.0–41.5%) as compared to peripheral blood B lymphocytes from 20 age‐matched, healthy individuals (median: 2.0%, range 0–6%; p < 0.001). The extent of centrosome aberrations correlated with the proliferative activity of the CLL cases as measured by lymphocyte doubling time (p = 0.02) as well as with time to first treatment (p = 0.05). Accordingly, more centrosome aberrations were found in PHA‐stimulated T lymphocytes from healthy individuals as well as in B cells from surgically removed tonsil tissue of patients with acute tonsillitis as compared to the peripheral blood B lymphocytes from the control group. In contrast, no correlation was observed between centrosome aberrations and immunoglobulin VH gene mutation status or cytogenetically defined risk groups. These findings suggest that, despite the common observation of most CLL cells remaining in G0/G1 phase, their centrosome replication process is deregulated and correlates to the proliferative activity of CLL cells. © 2007 Wiley‐Liss, Inc.

The presence of high‐risk chromosome aberrations in chronic lymphocytic leukaemia does not correlate with centrosome aberrations

“…Combining the observations by Hensel et al [7] and by Chiorazzi and Ferrarini [8], it could be expected that centrosome aberrations would be correlated to chromosome aberrations. However, neither Hensel et al [7] data nor our data, showed such a correlation.…”

“…deletions at 11q and 17p), and indeed cases with high numbers of CD38þ cells are enriched in chromosomal aberrations [15] and p53 dysfunction [16]. Combining the observations by Hensel et al [7] and by Chiorazzi and Ferrarini [8], it could be expected that centrosome aberrations would be correlated to chromosome aberrations. However, neither Hensel et al [7] data nor our data, showed such a correlation.…”

“…One study, quoted by Kraemer et al [6], found a significant correlation between the extent of structural centrosome abnormalities and the two major cytogenetic risk subgroups. More recently, however, Hensel et al [7] reported that no correlation was observed between centrosome aberrations and IgVH genes mutation status or cytogenetically defined risk groups. In our study, we did not detect any structural abnormality either in control or patient samples, but only in the cell line used as positive control for centrosome aberrations (AT Figure 1B).…”

“…This correlation clearly implied that lymphomas with a higher proliferation index displayed significantly more centrosome aberrations irrespective of the histological subgroup. In B-CLL, Hensel et al [7] found a correlation between centrosome aberrations and proliferation activity. In a recent review [8], it was suggested that since the CD38þ cells represent the major component of the proliferative compartment, these cells in particular might be more susceptible to developing chromosomal abnormalities (e.g.…”

“…Centrosome aberrations have recently been described in several different haematological malignancies like acute myeloid leukaemias, chronic myeloid leukaemias, myelodisplastic syndromes, lymphomas and multiple myelomas [6], but little is known about their occurrence and their possible role in B-CLL [7,8].…”