scholarly journals Karyotype-specific microRNA signature in chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3872-3879 ◽  
Author(s):  
Rosa Visone ◽  
Laura Z. Rassenti ◽  
Angelo Veronese ◽  
Cristian Taccioli ◽  
Stefan Costinean ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Variable Region ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Mutation Status ◽  
Ighv Gene ◽  
Trisomy 12 ◽  
Disease Initiation

Abstract Chromosomal abnormalities, immunoglobulin heavy chain variable–region (IGHV) gene mutation status, and ζ-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.

scholarly journals The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 329-337 ◽  
Author(s):  
Gianluca Gaidano ◽  
Davide Rossi
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Treatment Choice ◽  
Lymphocytic Leukemia ◽  
Prognostic Scores ◽  
Mutation Status ◽  
Biological Variables ◽  
Trisomy 12 ◽  
Innovative Drugs

Abstract The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHV genes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management. Other molecular predictors are under investigation, but their application in clinical practice is premature.

scholarly journals Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method

Blood ◽  
1992 ◽  
Vol 79 (7) ◽  
pp. 1796-1801 ◽  
Author(s):  
J Anastasi ◽  
MM Le Beau ◽  
JW Vardiman ◽  
AA Fernald ◽  
RA Larson ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Chronic Lymphocytic Leukemia ◽  
Fluorescence In Situ Hybridization ◽  
Cytogenetic Analysis ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Chromosome 12 ◽  
Interphase Cells ◽  
Trisomy 12

Abstract Trisomy 12 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and a number of studies have suggested that it may be an adverse prognostic indicator. We have evaluated the usefulness of fluorescence in situ hybridization with a chromosome 12- specific probe as a simple means for detecting trisomy 12 in interphase cells. Forty cases of B-cell CLL previously studied with conventional cytogenetic techniques were analyzed with a biotinylated probe to the centromeric region of chromosome 12. Thirty of these retrospective cases could be reevaluated with in situ hybridization. Our analysis showed three hybridization signals (ie, trisomy 12) in interphase cells from seven of seven cases found previously to have trisomy 12. Trisomy 12 was also detected in five additional cases: in one case thought to have a normal karyotype, in two cases that had been inadequate for routine cytogenetic analysis, and in two cases that had been found to have an abnormal karyotype without trisomy 12. In a prospective series of 20 newly accrued CLL cases, all cases were analyzed successfully by in situ hybridization and six (30%) showed trisomy 12. We were able to perform the analysis on routinely prepared and previously Wright- stained peripheral blood smears. We conclude that fluorescence in situ hybridization is a simple means for the detection of trisomy 12 in CLL. The technique is more sensitive than conventional cytogenetic analysis and would be a useful tool in clinical studies.

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

2006 ◽  
Vol 24 (6) ◽  
pp. 969-975 ◽  
Author(s):  
Alexander Kröber ◽  
Johannes Bloehdorn ◽  
Sebastian Hafner ◽  
Andreas Bühler ◽  
Till Seiler ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Characteristic Modes ◽  
Genomic Aberrations ◽  
Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

In Chronic Lymphocytic Leukemia Females Survive for Longer Than Males Even in Patients with Unmutated Immunoglobulin Genes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 16-16 ◽  
Author(s):  
Terry John Hamblin ◽  
Jenny A. Orchard ◽  
Zadie A. Davies ◽  
Rachel E. Ibbotson ◽  
Ann C. Gardiner ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Biology ◽  
Chromosomal Abnormalities ◽  
Alkylating Agents ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Free Survival ◽  
Significant Difference ◽  
Males And Females

Abstract Among the proposed prognostic factors for chronic lymphocytic leukemia (CLL), gender has been constant. In published trials females survive longer. With the new prognostic markers that relate to cell biology it seemed that an explanation was forthcoming. The sex ratio for patients with unmutated immunoglobulin variable region heavy chain (IgVH) genes is M:F=2:1 whereas for those with mutated IgVH genes it is close to unity. Females are less likely to have the more malignant subset. We have explored whether this is a sufficient explanation for the better outcome in females. 310 patients with CLL were studied. 260 were local patients representing the referral pattern of a district hospital and 50 were second-opinion referrals. 180 were male and 130 female. Overall, the median survival of females was 161 months compared to 119 months for males (p<0.005). 189 (101 males; 88 females) had mutated and 121 (79 males; 42 females) unmutated IgVH genes. As expected patients with mutated IgVH genes had longer median survivals (mutated 183 months, unmutated 95 months; p<0.0001). Thus males are more likely to belong to the shorter-lived subtype. However, this is not a complete explanation. Among those with unmutated IgVH genes, females also survived significantly longer (135 months versus 97 months; p<0.05), whereas among those with mutated IgVH genes there was no difference. Censoring for unrelated deaths did not affect the findings. We also looked at treatment-free survival. This was better for females than males (median time to treatment not yet reached versus 113 months; p=0.0097) but among those with unmutated IgVH genes there was no significant difference (49 months versus 31 months; p=0.57). However, survival following first treatment was significantly better for females than for males both for the whole group (127 months versus 70 months; p=0.0092) and for the unmutated subgroup (100 months versus 45 months; p=0.014), but there was no difference for the mutated group. This finding is consistent with the findings in clinical trials for which survival is calculated from date of entry into the trial, not date of diagnosis. There were other slight differences between males and females. Mean age at presentation was slightly greater for females (66.7 v 64.3; p=0.0063), and females who were treated were more likely to have received alkylating agents alone (20 males, 17 females; p=0.0015) but neither of these factors is likely to have led to greater longevity. 117 patients (86 males; 41 females) had required treatment. Apart from the group treated with alkylating agents alone there were no significant differences in how males and females were treated. 44 patients received an alkylating agent followed by fludarabine (30 males and 14 females), and 27 received a fludarabine containing regimen as first line (22 males and 5 females). Seven patients received monoclonal antibodies (5 male, 2 females) and there were 3 allografts (two male, one female) and 1 autograft (male). The prevalence of adverse chromosomal abnormalities as detected by FISH was 6.4% for 17p13 deletions and 12.3% for 11q23 deletions and not significantly different (separately or together) between the sexes. We conclude that females survive for longer following treatment for CLL for unknown reasons. We are aware that androgen receptors play a part in lymphopoiesis, but how this relates to the gender differences in CLL is unclear.

Influence of Chromosomal Aberrations on Response to First Line Therapy in B-Cell Chronic Lymphocytic Leukemia: Interim Analysis of PALG-CLL3 Randomized Study Comparing Cladribine Plus Cyclophosphamide vs Fludarabine Plus Cyclophosphamide.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2046-2046
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Ewa Wawrzyniak ◽  
Aleksandra Palacz ◽  
Joanna Gora-Tybor ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Aberrations ◽  
Interim Analysis ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Lower Probability ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Impact of cytogenetic abnormalities on treatment with different purine nucleoside analogs in patients (pts) with B-cell chronic lymphocytic leukemia (B-CLL) is largely unknown. One of objectives of PALG-CLL3 trial, comparing cladribine plus cyclophosphamide (CC) with fludarabine plus cyclophosphamide (FC) in previously untreated progressive B-CLL, was to verify the response to treatment in subsets of pts characterized by common cytogenetic abberrations. Chromosomal abnormalities were assessed using fluorescence in situ hybridization (FISH) on interphase nuclei of lymphocytes on whole blood smears prior to the start of the study treatment. Pts were screened for trisomy 12, deletions (del) 11q, del 13q and del 17p using DNA probes: CEP12, LSI: ATM, D13S319 and p53 (Vysis), respectively. For the purpose of the present interim analysis complete cytogenetic results were available in 133 pts out of 423 pts included to the study. In this group the chromosomal aberrations were detected in 102 pts (77%) including single abnormalities observed in 69 pts (52%) and two or more aberrations in 33 pts (25%). Thirty-one pts (23%) exhibited a normal interphase FISH pattern. The most frequent single abnormality was del 13q found in 38 pts (29%), while del 17p, trisomy 12 and del 11q were identified in 14 pts (11%), 11 pts (8%), and 6 pts, (5%), respectively. The most frequently observed associations of chromosomal aberrations were: del 13q with del 11q (11 pts, 8%) and del 13q with del 17p (10 pts, 8%). Four pts (3%) revealed three chromosomal abnormalities including association of trisomy 12/del 11q/del 13q in two pts, trisomy 12/del 11q/del 17p in one pt and del 11q/del 13q/del 17p in one pt. Overall, treatment was completed and response assessed in 113 out of 133 pts with known FISH pattern. In this group of pts del 17p was the only chromosomal abnormality that correlated significantly with treatment outcome. Pts with del 17p (21, 19%) had lower probability to achieve a complete response (CR) (0.044). Interestingly, in independent analyses of both treatment arms, the negative impact of 17p was seen in pts treated with FC (p=0.002), but not in pts treated with CC (p=0.6). Moreover, comparing response rates between treatment arms we found that CC was superior to FC in terms of complete response in pts with del 17p (57% CR in CC v 14% CR in FC arm, p=0.04). In conclusion, chromosomal abnormalities can be detected in majority B-CLL pts requiring treatment. Our preliminary results suggest that CC combination may have some advantage in terms of CR achievement in B-CLL pts harboring del 17p.

scholarly journals IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load

Haematologica ◽  
2021 ◽  
pp. 0-0
Author(s):  
Dianna Hussmann ◽  
Anna Starnawska ◽  
Louise Kristensen ◽  
Iben Daugaard ◽  
Astrid Thomsen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcomes ◽  
Lymphocytic Leukemia ◽  
Mutation Load ◽  
450K Array ◽  
Mutation Status ◽  
Classification Procedure ◽  
Array Data ◽  
Ighv Gene ◽  
Classification Procedures

Currently, no molecular biomarker indexes are used in standard care to make treatment decisions at diagnosis of chronic lymphocytic leukemia (CLL). We used Infinium MethylationEPIC array data from diagnostic blood samples of 114 CLL patients, and developed a patient stratification procedure based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment (TTT) with HR 8.34 (95% CI, 4.54-15.30), as opposed to HR 4.35 (95% CI, 2.60-7.28) for IGHV mutation status. Detailed evaluation of 17 discrepant cases between the two classification procedures showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (OS) (HR, 1.82; 95% CI, 1.07-3.09), which was not possible using IGHV status. Furthermore, we assessed the performance of the developed classification procedure using published HumanMethylation450 array data for 159 patients for which TTT, OS and relapse were available. Despite that 450K array methylation data did not contain all biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide improved prognostic power than IGHV mutation status.

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1848-1854 ◽  
Author(s):  
Terry J. Hamblin ◽  
Zadie Davis ◽  
Anne Gardiner ◽  
David G. Oscier ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Trisomy 12 ◽  
Vh Gene ◽  
Vh Genes ◽  
Variable Region Genes

Abstract Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed &gt;2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.

Role of microRNAs in Chronic Lymphocytic Leukemia Pathogenesis

2020 ◽  
Vol 27 (2) ◽  
pp. 282-297 ◽  
Author(s):  
Ehsan Javandoost ◽  
Ehsan Firoozi-Majd ◽  
Hosein Rostamian ◽  
Mohammad Khakpoor- Koosheh ◽  
Hamid Reza Mirzaei
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cellular Growth ◽  
Western World ◽  
Lymphoid Tissues ◽  
Cellular Processes ◽  
Trisomy 12 ◽  
Underlying Mechanisms

MicroRNAs (miRNAs) are a group of small endogenous non-coding RNAs involved in many cancers and various cellular processes such as cellular growth, DNA methylation, apoptosis, and differentiation. 13q14.3 chromosomal region contains miR-15 and miR-16 and deletion of this region is a commonly reported aberration in Chronic Lymphoblastic Leukemia (CLL), suggesting miRNAs involvement in CLL pathogenesis. MicroRNAs are known as oncogenes and tumor suppressors in CLL which may also serve as markers of onset and progression of the disease. The most prevalent form of leukemia diagnosed in adults in the western world, chronic lymphocytic leukemia, accounts for one-third of all leukemias. CLL is characterized by the presence of B Cell Malignant Clones in secondary lymphoid tissues, peripheral blood and bone marrow. The precise etiology of CLL is remained to be known, however, a number of Chromosomal Abnormalities such as deletions of 13q14.3, 11q and 17p and trisomy 12 have been detected. In this review, we offer our prospect on how miRNAs are involved in the CLL pathogenesis and disease progression. Further understanding of the underlying mechanisms and regulation of CLL pathogenesis has underscored the need for further research regarding their role in this disease.

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