Genetics of Chronic Lymphocytic Leukemia: Practical Aspects and Prognostic Significance (original) (raw)
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British Journal of Haematology, 1997
We analysed a group of 390 patients, diagnosed with chronic lymphocytic leukaemia (CLL). Cases were subclassified as morphologically typical and atypical CLL according to the criteria of the FAB proposal. Typical CLL cases were mostly diagnosed at a low-risk stage (Binet A/Rai 0), required no immediate treatment and expected a long survival; atypical CLL cases mostly presented at a more advanced risk stage (Binet B/Rai I-II), usually required immediate treatment and their survival was shorter. Moreover, clinical staging was of prognostic significance in typical but not in atypical cases.
Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis
Cellular Oncology, 2015
Backgrounds Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by a clonal accumulation of mature apoptosis-resistant neoplastic cells. It is also a heterogeneous disease with a variable clinical outcome. Here, we present a review of currently known (epi)genetic alterations that are related to the etiology, progression and chemo-refractoriness of CLL. Relevant literature was identified through a PubMed search of English-language papers using the terms CLL, signaling pathway, cytogenetic abnormality, somatic mutation, epigenetic alteration and micro-RNA. Results CLL is characterized by the presence of gross chromosomal abnormalities, epigenetic alterations, micro-RNA expression alterations, immunoglobulin heavy chain gene mutations and other genetic lesions. The expression of unmutated immunoglobulin heavy chain variable region (IGHV) genes, ZAP-70 and CD38 proteins, the occurrence of chromosomal abnormalities such as 17p and 11q deletions and mutations of the NOTCH1, SF3B1 and BIRC3 genes have been associated with a poor prognosis. In addition, mutations in tumor suppressor genes, such as TP53 and ATM, have been associated with refractoriness to conventional chemotherapeutic agents. Micro-RNA expression alterations and aberrant methylation patterns in genes that are specifically deregulated in CLL, including the BCL-2, TCL1 and ZAP-70 genes, have also been encountered and linked to distinct clinical parameters. Conclusions Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients.
Characteristic chromosome abnormalities in patients with chronic lymphocytic leukemia (CLL) have been shown to provide important prognostic information. Karyotyping and Fluorescence in situ hybridization (FISH) currently used in clinical diagnostics of CLL are targeted tests aimed at specific Cytogenetic marker. The aim of this study was to understand the role of the Cytogenetics and molecular Cytogenetic markers in Chronic Lymphocytic Leukemia through Cytogenetics techniques, i.e. Conventional Cytogenetics and FISH in a clinical diagnostic setting. Karyotyping and FISH were performed in all 15 CLL patients and compared with international prognostic scoring criteria. Here, we conclude that the clinical significance of cytogenetic examination in CLL is apparent. That most of patients with CLL show clonal Chromosomal aberrations (CAs) has become clearer with the ongoing approach of more sensitive detection methods. In CLL, there is a positive relationship between the presence of CAs and progressive disease, showing a prognostic role for cytogenetic investigations. The prognostic relevance of these Cytogenetics alterations requires further evaluation in prospective of targeted therapy.
Genetic Events in Chronic Lymphocytic Leukemia. A Review of the Literature
Medical Connections, 2017
The aim of this review is to present the latest researches in the field of molecular medicine in Chronic Lymphocytic Leukemia (CLL), emerged from the P53 gene deletion in human lymphoma genome. In recent years, the best technique in the investigation of malignant lymphocytes proved to be the Fluorescence in situ hybridization (FISH). This method is used as an alternative to chromosomal banding, a conventional application in molecular medicine. In the literature it was registered, in previous years, on an international study, conducted on 109 cases of CLL, 79 cases (72.5%) who had genetic abnormalities, the remaining 30 cases (27.5%) had normal results, using FISH technology. The majority of patients, 67% (53.79) had a single anomaly and the remaining 33% had two or three genetic abnormalities. The chromosomes 14q32/17p translocations in CLL genome, which appeared similar to some common, had demonstrated abnormalities involving IGH gene, located on chromosome14q32, responsible of hypogammaglobulinemia in some cases of CLL. Recent, endogenous somatic gene therapy research is a basis of a clinical and therapeutic trial. The DNA is used to treat a disease arising as a result of mutations in chromosomal regions. In the past few years, this method has been included in the treatment of CLL, acute lymphocytic leukemia, (ALL), or multiple myeloma (MM). The frequencies of p53 gene mutations and deletion in CLL can be categorized as individual biomarkers in proteomic and genomic profile for this type of leukemia that can be implemented in targeted patient treatment of personalized medicine.
GENETIC EVENTS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Aim of this study is to present the latest researches in the field of molecular medicine, in terms of Chronic Lymphocytic Leukemia (CLL), emerged from the P53 gene deletion in human lymphoma genome. Method In recent years proved that the best technique in the investigation of malignant lymphocytes is the Fluorescence in situ hybridization (FISH). This method is used as an alternative to chromosomal banding, a conventional application in molecular medicine. Previous results: In the literature it was registered, in previous years, on an international study, conducted on 109 cases of CLL, 79 cases (72.5%) who had more genetic abnormalities: the remaining 30 cases (27.5%) had normal results, using FISH technology. The majority of patients, 67% (53.79) had a single anomaly and the remaining 33% had two or three genetic abnormalities. The chromosomes 14q32 /17p translocations in LLC genome, which appeared similar to some common, had demonstrated abnormalities involving IGH gene, located on chromosome14q32. Discussion Recent, endogenous somatic gene therapy research is a basic of trial clinical and therapeutic trial. The DNA, is used to treat a disease arising as a result of mutations in chromosomal regions. In the past few years, this method has been included in the treatment of CLL, acute lymphocytic leukemia, [ALL], or multiple myeloma [MM]. Conclusion The frequencies of P53 gene mutations and deletion in CLL can be categorized as individual biomarkers in proteomic and genomic profile for this type of leukemia that can be implemented in targeted patient treatment of personalized medicine. Keywords: P-53 Gene, Lymphocytic Leukemia, Apoptosis, Fluorescence in Situ Hybridization
Leukemia, 2005
Chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) have been shown to correlate with prognosis. Little is known about the relationship between chromosomal abnormalities and biological behavior of B-CLL cells in vitro. The present study was designed to explore the impact of chromosomal abnormalities determined by interphase fluorescence in situ hybridization (FISH) on the in vitro survival and immunogenicity of B-CLL. Considerable heterogeneity was noted in the in vitro survival and expression of costimulatory, adhesion, and antigen-presenting molecules by B-CLL cells. Spontaneous apoptosis of B-CLL cells in vitro was significantly lower in samples with good prognosis cytogenetics when compared to samples with poor prognosis cytogenetics. In contrast, B-CLL cells from samples with good prognosis cytogenetics exhibited higher basal expression of molecules involved in costimulation, cellular adhesion, and antigen presentation, and induced significantly more T-cell proliferation in mixed lymphocyte cultures. We conclude that chromosomal aberrations of B-CLL cells correlate with the in vitro biological behavior of B-CLL. Our data indicate that good prognosis cytogenetics correlates with less spontaneous apoptosis but greater in vitro immunogenicity. These findings could have significant implications on the design of future therapeutic approaches in patients with CLL, and the likelihood of response based on cytogenetics.
Indian Journal of Cancer, 2013
BACKGROUND: The present study of 238 B-cell Chronic Lymphocytic Leukemia (B-CLL) patients were undertaken to seek the prevalence and to evaluate clinico-pathological significance of recurrent genetic abnormalities such as del(13q14.3), trisomy 12, del(11q22.3) (ATM), TP53 deletion, del(6q21) and IgH translocation/deletion. MATERIALS AND METHODS: We applied interphase-fluorescence in situ hybridization (FISH) on total 238 cases of B-CLL. RESULTS: Our study disclosed 69% of patients with genetic aberrations such as 13q deletion (63%), trisomy 12 (28%), 11q deletion (18%), 6q21 deletion (11%) with comparatively higher frequency of TP53 deletion (22%). Deletion 13q displayed as a most frequent sole abnormality. In group with coexistence of ≥2 aberrations, 13q deletion was a major clone indicating del(13q) as a primary event followed by 11q deletion, TP53 deletion, trisomy 12, 6q deletion as secondary progressive events. In comparison with del(13q), trisomy 12, group with coexistence of ≥2 aberrations associated with poor risk factors such as hyperleukocytosis, advanced stage, and multiple nodes involvement. In a separate study of 116 patients, analysis of IgH abnormalities revealed either partial deletion (24%) or translocation (5%) and were associated with del(13q), trisomy 12, TP53 and ATM deletion. Two of 7 cases had t(14;18), one case had t(8;14), and four cases had other variant IgH translocation t(?;14). CONCLUSION: Detail characterization and clinical impact are necessary to ensure that IgH translocation positive CLL is a distinct pathological entity. Our data suggests that CLL with various cytogenetic subsets, group with coexistence of ≥2 aberrations seems to be a complex cytogenetic subset, needs more attention to understand biological significance and to seek clinical impact for better management of disease.
Blood, 2003
disease show distinctive phenotypic and genotypic features Chronic lymphocytic leukemia patients with highly stable and indolent http://bloodjournal.hematologylibrary.org/content/102/3/1035.full.html Updated information and services can be found at: (4217 articles) Neoplasia (5012 articles) Immunobiology (3712 articles) Clinical Trials and Observations Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests
American Journal of Pathology, 2002
Chromosomal imbalances were examined by comparative genomic hybridization in 30 cases of B-cell chronic lymphocytic leukemia (CLL) at diagnosis, in sequential samples from 17 of these patients, and in 6 large B-cell lymphomas transformed from CLL [Richter's syndrome (RS)] with no available previous sample. The most common imbalances in CLL at diagnosis were gains in chromosome 12 (30%), and losses in chromosomes 13 (17%), 17p (17%), 8p (7%), 11q (7%), and 14q (7%). The analysis of sequential samples showed an increased number of chromosomal imbalances in 6 of 10 (60%) patients with clinical progression and in 2 patients with stable stage C disease. No karyotypic evolution was observed in four cases with stable stage A disease and in one RS clonally unrelated to the previous CLL. Gains of 2pter, and 7pter, and losses of 8p, 11q, and 17p were recurrent alterations associated with karyotype progression. RS showed a higher number of gains, losses, total alterations, and losses of 8p and chromosome 9 than CLL at diagnosis. 17p losses were associated with p53 gene mutations and with a significantly higher number of chromosomal imbalances than tumors with normal chromosome 17 profile. However, no relationship was observed between 9p deletions and p16 INK4a gene alterations. Losses of 17p and an increased number of losses at diagnosis were significantly associated with a shorter survival. These findings indicate that CLL has frequent chromosomal imbalances, which may increase during the progression of the disease and transformation into large cell lymphoma. Genetic alterations detected by comparative genomic hybridization may also be of prognostic significance. B-cell chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adults and accounts for Ͼ30% of all leukemia cases in Europe and North America. CLL is characterized by clonal proliferation and accumulation of mature-appearing neoplastic B lymphocytes. Clonal chromosome aberrations are detected in ϳ40 to 50% of CLL cases by conventional cytogenetics and approximately half of the patients show single abnormalities. In contrast to other lymphoproliferative disorders, CLL has a very low frequency of chromosomal translocations involving immunoglobulin genes and the most frequent genetic abnormalities are losses of 13q and 11q, trisomy 12, and losses of 6q and 14q. 1-4 Fluorescence in situ hybridization (FISH) studies in interphase cells have shown the presence of cell clones carrying chromosomal aberrations in cases in which no abnormalities were found by banding analysis. 5 Using this technique, clonal aberrations can be detected in Ͼ80% of cases. 2 However, only a few chromosomal regions can be examined in a single experiment by interphase FISH. Conversely, comparative genomic hybridization (CGH) allows a rapid analysis of chromosomal imbalances within the tumor genome without the requirement of cell culturing and metaphase preparation.