Genetic Features of B‐Cell Chronic Lymphocytic Leukemia

Abstract

The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.

CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases

“…Furthermore, trisomy 12 has also been described as a recurrent anomaly in SMZL. 15 The observed IGHV mutation pattern was also distinct from that in CLL, with more cases mutated (80% versus 50%) and the VH1-2*04 segment, previously identified in SMZL 16,27,28 and present here in 20% of the cases, is very infrequent in CLL (4%). 27 Furthermore, no ongoing mutation was observed and the length of the CDR3 was variable, contrasting with the findings in CLL.…”

Chromosomal abnormalities detected by multicolor fluorescence in situ hybridization in fine-needle aspirates from patients with small lymphocytic lymphoma are useful for predicting survival

“…This abnormality is demonstrated in 7% to 16% of CLL cases. 1,8,13,15 The 17p13 locus contains several genes associated with cell regulatory functions, including the p53 tumor suppressor gene, which plays a key role in the regulation of apoptosis. With loss of this apoptotic gene, cells may continue to survive and proliferate, resulting in increased genetic abnormalities.…”

“…[3][4][5][6] Chronic lymphocytic leukemia (CLL), which may include SLL as part of the disease spectrum, has chromosomal aberrations in 16% to 82% of cases, depending on the type of analysis. [6][7][8][9] Interphase fluorescence in situ hybridization (FISH) has an enhanced ability over conventional cytogenetics to detect specific chromosomal abnormalities 7,8 ; however, to our knowledge only a limited number of specific chromosomal abnormalities can be analyzed as a routine laboratory test. 5,7 A 2-panel multicolor FISH probe designed to aid in the diagnosis of CLL detects chromosomal anomalies of chromosomes 11q22 (ATM gene), 12, 13q14.3, 13q34.3 (LAMP1 gene), and 17p13.1 (p53 gene) and is commercially available.…”

Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706

“…Eight of the 11 abnormal cases contained one or more of these chromosome abnormalities, all of which have been previously reported to be common abnormalities observed in CLL. 22 Analysis of the cytogenetic data was inconclusive due to the small sample size.…”