The role of cytogenetic and molecular testing in the diagnostics and prognostication of chronic B-cell lymphocytic leukemia

2021 ◽  
Vol 56 (3) ◽  
pp. 1-17
Author(s):  
Marta Szarawarska ◽  
Andrzej Jasiewicz ◽  
Andrzej Pluta ◽  
Joanna Niemiec
Keyword(s):  
B Cell ◽  
Predictive Factors ◽  
Chromosomal Abnormalities ◽  
Adult Population ◽  
Clinical Stage ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Molecular Testing ◽  
Mutational Status ◽  
Risk Patients

B-cell chronic lymphocytic leukemia (B-CLL) is the most frequently diagnosed leukemia in an adult population in Europe and North America. Disease pathogenesis is not well defined. The majority patients are following the “wait and watch” strategy since early treatment does not affect survival. The therapeutic decision is based on the clinical stage of disease, presence of comorbid conditions clinical disease activity as well as 11q deletion and 17p deletion status and/or mutation in the TP53 gene. Moreover, expression of CD38, ZAP70, and mutational status of IGVH gene are well-known prognostic factors. The following chromosomal abnormalities are the most frequently diagnosed in CLL: 13q14 (in 50 – 60% CLL), 11q22-23 (in 12 – 18% CLL), 17p13 (in 10% CLL) deletion, 6q (in about 6% CLL) and trisomy of chromosome 12 (in 10 – 20% CLL). However, the above-mentioned factors are not able to define all, high-risk patients. Therefore, there is an urgent need to search for new prognostic and predictive factors, which might be helpful in better classification and selection for personalized therapy for B-cell CLL patients. This prompted us to review both the well-known and new prognostic/predictive factors.

ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3584-3592 ◽  
Author(s):  
Sarah J. Richardson ◽  
Christine Matthews ◽  
Mark A. Catherwood ◽  
H. Denis Alexander ◽  
B. Sean Carey ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Actin Polymerization ◽  
Chromosomal Abnormalities ◽  
Lymphocytic Leukemia ◽  
Cellular Migration ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

Molecular markers like IgVH mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70+ CLL B cells respond in vitro more readily than ZAP-70– CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70+ CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-α, a survival factor produced by stromal cells) compared with ZAP-70– cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70+ but not ZAP-70– CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70+ disease.

The t(14;19)(q32;q13) Translocation in B Lymphoproliferative Disorders: A Continuum from Chronic Lymphocytic Leukemia (CLL) to Marginal Zone Lymphoma (MZL)?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4944-4944
Author(s):  
Florence Nguyen-Khac ◽  
Elise Chapiro ◽  
Isabelle Radford-Weiss ◽  
Christian Bastard ◽  
Leroux Dominique ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Abnormalities ◽  
B Cell Lymphoma ◽  
Biological Data ◽  
Lymphocytic Leukemia ◽  
Recurrent Event ◽  
Fish Analysis ◽  
Mutational Status ◽  
Independent Analysis ◽  
7Q Deletion

Abstract Translocation t(14;19)(q32;q13) juxtaposing BCL3 in 19q13 with IGH in 14q32, is a rare recurrent event found in patients with B-cell malignancies. So far, a few cases of well-documented B-cell neoplasm have been reported. We analyzed 34 patients with t(14;19) and 1 patient with a variant t(2;19)(p11;q13) collected by the Groupe Francophone de Cytogenetique Hematologique on the basis of cytogenetic abnormality. Clinico-biological data, morphological review, immunophenotyping with Matutes’ score, conventional karyotype and FISH analysis with BCL3, IGH, CEP12, 13q14, ATM, TP53, 6q21 probes, and IgVH mutational status were recorded. The sex ratio was 22M/13F, the median age at diagnosis was 61 [39–89], the lymphocyte count was &gt; 4×109/l in 96% of patients, and spleen enlargement was found in 47%. 31% (11/35) were morphologically classified CLL, 37% (13/35) atypical CLL, 20% (7/35) MZL; 79% had features of disease progression; 3 of the 4 latter were Diffuse Large B Cell Lymphoma, possibly transformed from MZL. 87% were CD5+, 72% had a Matutes’ score &lt; 3. The IgVH genes were unmutated in 9/11 cases. The time to treatment was &lt; 1 year in 68% of patients. The BCL3 locus involvement was confirmed by FISH analysis in all cases. 46% of cases showed complex karyotype. The chromosomal abnormalities associated with t(14;19) were +12 (57%), 6q- (27%), +3 (15%), 11q- (15%), 13q- (13%), 17p- (12%), +18 (12%), 7q- (12%). Comparison with published cytogenetic CLL data shows that deletion 6q was frequent and deletion 13q uncommon. Trisomies 3 and 18, and 7q deletion are less common than in published MZL. The independent analysis of our series of CLL/atypical CLL and MZL gave the same tendency. The chromosomal abnormalities associated with t(14;19) are not specific, but their frequencies are between those of typical CLL and MZL suggesting an intermediary status between the 2 malignancies. The t(14;19) identifies a subgroup of B-disorders CD5+ and Matutes’ score &lt; 3, which could be of poor prognosis, based on progressive disease and unmutated status.

CD26 Expression in Mature B-Cell Neoplasia: Its Possible Role as a New Prognostic Marker in B-CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4670-4670
Author(s):  
Lilla Cro ◽  
Nadia Zucal ◽  
Sonia Fabris ◽  
Antonino Neri ◽  
Marta Lionetti ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Abnormalities ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Favourable Outcome ◽  
Lymphocytic Leukemia ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Mutational Status ◽  
Cd26 Expression

Abstract CD26 (dipeptidyl peptidase IV, DPP IV) is a multifunctional type II cell surface glycoprotein that is widely expressed on T and natural killer cells, as well as on epithelial, endothelial and acinar cells of different tissues; its expression on B cells is very low but it is greatly upregulated following activation. We evaluated, by means of flow cytometry, the expression of CD26 in various types of B-cell lymphoid tumors: Follicular Lymphoma (Fo-Ly, 12 cases), Mantle cell Lymphoma (MCL, 12 cases) Multiple Myeloma (MM, 20 cases), Hairy cell Leukemia (HCL, 12 cases), B-cell Chronic Lymphocytic Leukemia (B-CLL, 112 cases), CD5 negative B-cell Chronic Lymphoproliferative Diseases (CD5neg-B-CLPD, 20 cases) and Diffuse Large cell Lymphoma (DLCL, 12 cases). CD26 expression was absent or low of Fo-Ly and MCL, high on MM and HCL, variable on B-CLL, CD5neg-B-CLPD and DLCL. Fluorescence intensity of positive cells was dim in B-CLL and CD5neg-B-CLPD, heterogeneous in DLCL, and bright in HCL and MM. Interestingly, in CLL patients, CD26 expression was significantly correlated with CD49d and CD38 expressions (p<0.0001); moreover Spearman’s test revealed a significant correlation between CD26, CD38 or ZAP-70 expression and IgVH mutational status (p<0.0001). We also found a significant correlation between CD26 expression and the presence of FISH chromosomal abnormalities grouped on the basis of their prognostic relevance (p<0.0001). After a median follow-up of 36 months, 65/107 CLL pts were treated; taking 10% of positive cells as best cut-off, Kaplan-Meier curves showed that the time without therapy was significantly longer for CD26 negative cases compared with CD26 positive cases (P <0.0001). Moreover the concordant negativity of CD26 and CD38, or ZAP-70 and the combination of CD26 negativity with IgVH mutated status, identified subsets of CLL patients with a favourable outcome in terms of need of therapy.

scholarly journals Clinical significance of TP53 aberrations and IGHV mutational status in chronic lymphocytic leukemia

2020 ◽  
Vol 71 (4) ◽  
pp. 47-53
Author(s):  
Kristina Tomić ◽  
Teodora Karan-Đurašević ◽  
Vojin Vuković ◽  
Biljana Mihaljević ◽  
Darko Antić
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Predictive Factors ◽  
Clinical Course ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Resistant Disease ◽  
Mutational Status ◽  
Variable Gene ◽  
The One ◽  
Prognostic And Predictive Factors

Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease with a variable clinical course. On the one side of the spectrum, there are patients with aggressive and resistant disease, of which they die only a few months after diagnosis while, on the other side, there are patients with an indolent, slowly progressive disease that does not require treatment for decades. The reasons for this are only partially known, but they have been the subject of numerous scientific studies during the last several decades. Consequently, the concept of prognostic and predictive factors in CLL have emerged, which aims to predict the clinical course and its therapeutic outcome. With the improvement of understanding the pathophysiology of this disease, the lists of prognostic and predictive factors are getting longer every year, but they also overlap. In this review, we singled out the aberrations of the TP53 gene and the IGHV (immunoglobulin heavy variable) gene mutational status as the two most important and most studied factors that have both prognostic and predictive significance.

scholarly journals Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

2001 ◽  
Vol 194 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Andreas Rosenwald ◽  
Ash A. Alizadeh ◽  
George Widhopf ◽  
Richard Simon ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Gene Expression Signature ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Human Leukemia ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

scholarly journals Emergence of a B-cell lymphoblastic lymphoma in a patient with B-cell chronic lymphocytic leukemia: evidence for the single-cell origin of the two tumors

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 797-804
Author(s):  
V Pistoia ◽  
S Roncella ◽  
PF Di Celle ◽  
M Sessarego ◽  
G Cutrona ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Peripheral Blood ◽  
Chromosomal Abnormalities ◽  
Cell Clone ◽  
Lymphoblastic Lymphoma ◽  
Lymphocytic Leukemia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Chain Gene

A patient is described who presented with a chronic lymphocytic leukemia (CLL) and later developed a lymphoblastic lymphoma. The cells from the CLL were typical mature B lymphocytes as could be assessed by morphologic, cytochemical, and surface marker analyses. The cells from the lymphoblastic lymphoma were immature B cells that expressed CD10, CD20, and HLA-DR markers, but not surface Ig or cytoplasmic mu chains, and were negative for terminal deoxynucleotidyl transferase (TdT). The cells of two continuous cell lines, obtained from the bone marrow and the peripheral blood of the patient, had the same phenotype as the lymphoblastic lymphoma cells, did not contain the Epstein-Barr virus genome, and displayed malignant features in vitro, including the capacity to form colonies in agar. The two cell lines also shared identical chromosomal abnormalities, a finding which suggests that they derived from the same malignant cell already present in vivo. Such chromosomal abnormalities were not seen in the karyotype of the peripheral blood cells at the onset of the disease. Analysis of the Ig heavy chain genes using a DJ-specific probe showed the very same monoclonal rearrangement in the cells from the B-CLL, the lymphoblastic lymphoma and the two cell lines, thus demonstrating their common clonal origin. By contrast, a monoclonal rearrangement of the lambda chain gene locus was found in the B-CLL cells only, a finding consistent with their exclusive capacity to express surface IgM lambda. This patient represents a rare case in whom a chronic lymphoproliferative disorder with mature malignant cells transforms into a lymphoblastic lymphoma characterized by cells frozen at a very early maturational stage. The possible mechanisms leading to such transformation within the same cell clone are discussed.

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344 ◽  
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

2011 ◽  
Vol 29 (16) ◽  
pp. 2223-2229 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Hockley ◽  
David Oscier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Data ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

FMNL-1 (Formin-Like 1) Gene in Chronic Lymphocytic Leukemia (CLL) Is Overexpressed in Young Patients with Adverse Prognostic Factors and Poor Outcome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2775-2775 ◽  
Author(s):  
Eva Calpe ◽  
Patricia M.B. Favaro ◽  
Marta Crespo ◽  
Maria Joao Baptista ◽  
Ana Muntañola ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Survival ◽  
Lymphocyte Count ◽  
Biological Diversity ◽  
Young Patients ◽  
Lymphocytic Leukemia ◽  
Time To Progression ◽  
Mutational Status ◽  
Wide Range

Abstract Prognosis of patients with CLL has been traditionally assessed by using clinical parameters. Although useful, such parameters are a mere reflection of the biological diversity of CLL. In this regard, the mutational status of VH genes or ZAP-70 expression separates CLL into two clinical forms with different presenting features and outcome. Formins are multidomain proteins characterized by the presence of two conserved prolin-rich regions, namely formin homology 1 and 2. These proteins are implicated in a wide range of processes, including regulation of the cytoskeleton and in the regulation of the signal for cell survival. Formin is normally expressed in spleen, lymph node, and bone marrow cells, and it has been recently found to be overexpressed in T-cell lymphomas. The aim of this study was to analyze the expression of FMNL-1 in normal B-cell subsets and in a series of 73 patients (median age, 59 years; male/female 40/33; Binet A: 90.2%) with CLL. FMNL-1 expression was analyzed by Western Blot in separate subpopulations and by quantitative RT-PCR using expression in Jurkat as baseline. Among normal lymphocytes, FMNL-1 was only expressed in memory (CD19+CD27+) B-cells and in T-cells. In CLL cases with a low percentage of T-cells, mean of FMNL-1 expression was 2.18 AU (SD, 1.01 AU). Using an arbitrary cut-off of 3.2 AU, cases with increased expression of FMNL-1 were associated with a younger age at diagnosis (< 50 yrs), elevated lymphocyte count, high serum β2-microglobulin (β2-m) levels, increased ZAP-70 and CD38 expression, shorter time to progression, and shorter survival as compared to cases with low FMNL-1 expression. No relationship was observed with genetic abnormalities (table). In summary, among B-cell lymphoproliferative disorders, FMNL-1, a gene that regulates cell survival, is found only in CLL and its overexpression correlates with adverse clinical and biological parameters, particularly in young patients. Variable FMNL-1 normal FMNL-1 increased p value Age < 50 yrs 15% 86% 0.0001 Lymphocyte count > 50.000/ μL 14% 57% 0.018 Increasedβ2-microglobulin 17% 66% 0.038 CD38 > 30% 28% 100% 0.001 ZAP-70≥20% 50% 100% 0.014 Time to progression (median) 5.1 yrs 0.5 yrs 0.003 Survival (median) 16.4 yrs 8.5 yrs 0.009

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