scholarly journals RNA Editing Alters miRNA Function in Chronic Lymphocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1159 ◽  
Author(s):  
Franz J. Gassner ◽  
Nadja Zaborsky ◽  
Daniel Feldbacher ◽  
Richard Greil ◽  
Roland Geisberger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Rna Editing ◽  
Treatment Resistance ◽  
Lymphocytic Leukemia ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Survival Times ◽  
Specific Expression ◽  
B Cell Leukemia ◽  
Specific Expression Pattern

Chronic lymphocytic leukemia (CLL) is a high incidence B cell leukemia with a highly variable clinical course, leading to survival times ranging from months to several decades. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression levels of genes by binding to the untranslated regions of transcripts. Although miRNAs have been previously shown to play a crucial role in CLL development, progression and treatment resistance, their further processing and diversification by RNA editing (specifically adenosine to inosine or cytosine to uracil deamination) has not been addressed so far. In this study, we analyzed next generation sequencing data to provide a detailed map of adenosine to inosine and cytosine to uracil changes in miRNAs from CLL and normal B cells. Our results reveal that in addition to a CLL-specific expression pattern, there is also specific RNA editing of many miRNAs, particularly miR-3157 and miR-6503, in CLL. Our data draw further light on how miRNAs and miRNA editing might be implicated in the pathogenesis of the disease.

scholarly journals Germline Allele-Specific Expression of DAPK1 in Chronic Lymphocytic Leukemia

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e55261 ◽  
Author(s):  
Quan-Xiang Wei ◽  
Rainer Claus ◽  
Thomas Hielscher ◽  
Daniel Mertens ◽  
Aparna Raval ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Allele Specific

scholarly journals V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1410-1416 ◽  
Author(s):  
Alexander Kröber ◽  
Till Seiler ◽  
Axel Benner ◽  
Lars Bullinger ◽  
Elsbeth Brückle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Chain Gene ◽  
P Value ◽  
Prognostic Impact ◽  
Survival Times ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

scholarly journals Autoimmune Thrombocytopenic Purpura ("ITP" Type) with Chronic Lymphocytic Leukemia

Blood ◽  
1962 ◽  
Vol 19 (1) ◽  
pp. 23-37 ◽  
Author(s):  
SHIRLEY EBBE ◽  
BENJAMIN WITTELS ◽  
WILLIAM DAMESHEK
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Survival Times ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Thrombocytopenic Purpura ◽  
Antiplatelet Antibodies ◽  
Platelet Survival

Abstract Five cases of chronic lymphocytic leukemia complicated by thrombocytopenic purpura are presented. They differed from the usual cases with this complication in that megakaryocytes were plentiful in spite of leukemic involvement of the bone marrow. Hypersplenism did not appear to be a factor. The evidence suggests that the thrombocytopenia was of an autoimmune nature, due to antiplatelet antibodies. Brief platelet survival times, the presence of a platelet agglutinin, staining of megakaryocytes by fluorescein-labeled anti-human globulin, and responses to corticosteroids were demonstrated.

scholarly journals A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1422-1425 ◽  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Randomized Clinical Trial ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Cooperative Group ◽  
Survival Times ◽  
Treatment Groups ◽  
Significant Difference

Abstract In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which intermediate prognosis patients (stage B) received either an indefinite course of chlorambucil (0.1 mg/kg/d) or 12 cycles of the COP regimen (vincristine, cyclophosphamide, and prednisone). We present the results of the third interim analysis based on 291 patients (151 in the chlorambucil group and 140 in the COP group) with a mean follow-up of 53 months at the reference date of June 1, 1987. At this date, 129 deaths were observed, 65 in the chlorambucil group and 64 in the COP group; there was no improvement in overall survival with the COP regimen (P = .44) even after adjusting for both prognostic and imbalanced factors (P = .24). The 3-year and 5-year overall survival rates were, respectively, 69% and 44% in the chlorambucil group as compared with 73% and 43% in the COP group. The median survival times were 58 months in the chlorambucil group and 57 months in the COP group. Moreover, no significant difference was observed between the two treatment groups in terms of either treatment response, 9-month status, time to disease progression to stage C, or causes of death.

Allotransplantation for chronic lymphocytic leukemia

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 602-609 ◽  
Author(s):  
Peter Dreger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Modulation ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Lymphocytic Leukemia ◽  
Successful Outcome ◽  
Mortality And Morbidity ◽  
Poor Risk ◽  
Leukemic Clone

AbstractEfforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.

scholarly journals Clinical staging of chronic lymphocytic leukemia

Blood ◽  
1975 ◽  
Vol 46 (2) ◽  
pp. 219-234 ◽  
Author(s):  
KR Rai ◽  
A Sawitsky ◽  
EP Cronkite ◽  
AD Chanana ◽  
RN Levy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Prognostic Significance ◽  
Stage Iv ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Stage Ii ◽  
Stage Iii ◽  
Clinical Staging ◽  
Survival Times

A method of clinical staging of chronic lymphocytic leukemia (CLL) has been proposed which is based on the concept that CLL is a disease of progressive accumulation of nonfunctioning lymphocytes: stage O, bone marrow and blood lymphocytosis only; stage 1, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia. Analysis of 125 patients. in the present series showed the following median survival times (in months) from diagnosis: stage 0, is greater than 150; stage I 101; stage II, 71; stage III, 19; stage IV, 19, The median survival for the entire series was 71 mo. The prognostic significance of the stage remained even after adjustment was made for age and sex. However, both sex and age were shown to be poor predictors of survival after adjustment for stage. The method of staging proved to be a reliable predictor of survival whether used at diagnosis or during the course of the disease. The proposed staging system was an equally accurate indicator for survival when applied to two other previously published studies of large series of patients.

scholarly journals A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1422-1425 ◽  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Randomized Clinical Trial ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Cooperative Group ◽  
Survival Times ◽  
Treatment Groups ◽  
Significant Difference

In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which intermediate prognosis patients (stage B) received either an indefinite course of chlorambucil (0.1 mg/kg/d) or 12 cycles of the COP regimen (vincristine, cyclophosphamide, and prednisone). We present the results of the third interim analysis based on 291 patients (151 in the chlorambucil group and 140 in the COP group) with a mean follow-up of 53 months at the reference date of June 1, 1987. At this date, 129 deaths were observed, 65 in the chlorambucil group and 64 in the COP group; there was no improvement in overall survival with the COP regimen (P = .44) even after adjusting for both prognostic and imbalanced factors (P = .24). The 3-year and 5-year overall survival rates were, respectively, 69% and 44% in the chlorambucil group as compared with 73% and 43% in the COP group. The median survival times were 58 months in the chlorambucil group and 57 months in the COP group. Moreover, no significant difference was observed between the two treatment groups in terms of either treatment response, 9-month status, time to disease progression to stage C, or causes of death.

Expert Variant Curation Combined with in-Silico analysis for Clinical Interpretation of BCL2 variants in Resistance to BCL2 Inhibitors in Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Matthew McCoy ◽  
Shruti Rao ◽  
Shannon Cosgrove ◽  
Subha Madhavan ◽  
Shashikant Kulkarni ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Significance ◽  
In Silico ◽  
Computational Models ◽  
Treatment Resistance ◽  
In Silico Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Clinical Interpretation ◽  
Silico Analysis

Venetoclax is an oral, highly selective, BCL2 inhibitor approved by the FDA for use in chronic lymphocytic leukemia/small lymphocytic lymphoma and acute myeloid leukemia. Despite favorable responses, multiple biological mechanisms lead to treatment resistance. One such mechanism includes somatic mutations in the BCL2 gene. Multiple lines of evidence suggest that hot-spot mutations in BCL2 such as Gly101Val induce treatment resistance by disrupting the binding of BCL2 to the BCL2 inhibitors such as venetoclax. Further, widespread use of high-throughput NGS technologies has identified multiple BCL2 mutations and additional concurrent molecular alterations at various variant allele frequencies in patients with progression while undergoing venetoclax therapy. In order to understand and determine the clinical significance of each of these mutations, careful expert curation and integration into somatic variant annotation AMP/ASCO/CAP guidelines is needed. Further, curation of those somatic variants that may not have sufficient functional evidence in literature may benefit from additional tools such as in silico analysis. To address these issues, we have undertaken an effort to integrate the contributions of a multidisciplinary expert panel (clinical laboratory diagnosticians, oncologists, biomedical informaticians and lab-based researchers) for curation of BCL2 variants in hematological malignancies under the umbrella of ClinGen, an NIH/NHGRI funded consortium to establish standards and centralized resources for assessing the clinical significance of gene variants. Within the ClinGen Somatic Cancer Clinical Domain Working Group (CDWG) ((https://www.clinicalgenome.org/working-groups/somatic/), the somatic hematological malignancy taskforce has identified 56 peer-reviewed publications on BCL2 inhibitors (Jan 2014 to June 2020). The functional evidence contained within these publications was curated using CIViC (Clinical Interpretation of Variants in Cancer, civicdb.org), an open access, crowdsourced aggregation of expert curated evidence. Only a fraction of the somatic variants identified in BCL2 has established functional evidence on variant induced disruption to Venetoclax inhibition. Curation of these remaining variants of unknown significance (VUS) only have in silico functional assays to provide evidence on their potential resistance to Venetoclax. The current curation guidelines do not consider in silico prediction as a strong line of evidence for the interpretation of somatic sequence variants, however this recommendation is meant to interpret generalized in silico predictors and not robust computational models of specific protein function. The latter are more comparable to an experimental functional assay, and provide curators with more trustworthy computational assessments of disruption to protein specific functions. In order to assess their potential to integrate and supplement experimental evidence, the interaction of Ventoclax with several drug resistant BCL2 variants was simulated using AutoDock Vina (J Comput Chem. 2010;31(2):455-61). Facilitated by the SNP2SIM workflow (BMC Bioinformatics. 2019;20(1):171), the relative impact on binding energy was compared to the wildtype system. The in silico binding assay accurately predicted resistance (Fig 1), and demonstrates the utility of applying these methods to the large number of VUS in BCL2. In conclusion, the evidence-based expert curation of BCL2 variants provides a standardized approach for reporting and interpretation across all labs. For those variants (Tier 3) with limited published evidence, computational models that can predict specific changes to functional protein interactions can provide additional tools to the expert curators. Development and incorporation of these tools into curation guidelines requires the refinement of the predictive models through focused validation studies. Disclosures No relevant conflicts of interest to declare.

Reduced Expression of Adhesion Molecules and Cell Signaling Receptors by Chronic Lymphocytic Leukemia Cells With 11q Deletion

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 624-631 ◽  
Author(s):  
Sabine Sembries ◽  
Heike Pahl ◽  
Stephan Stilgenbauer ◽  
Hartmut Döhner ◽  
Folke Schriever
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Signaling ◽  
Adhesion Molecules ◽  
Lymphocytic Leukemia ◽  
Survival Times ◽  
Rapid Disease Progression ◽  
Surface Molecules ◽  
Complement Receptor 1 ◽  
Signaling Receptors ◽  
11Q Deletion

Deletions in chromosome bands 11q22-q23 were recently shown to be one of the most frequent chromosome aberrations in B-cell chronic lymphocytic leukemia (B-CLL). Patients suffering from B-CLL with 11q deletion are characterized by extensive lymphadenopathy, rapid disease progression, and short survival times. Phenotypic and functional characteristics of B-CLL cells with 11q deletion that may help to explain the pathophysiology of this entity are yet unknown. In the present study, B-CLL cells with (n = 19) and without (n = 19) 11q deletion were analyzed for their expression of functionally relevant cell surface molecules (n = 57). B-CLL cells with 11q deletion carried significantly lower levels of the adhesion molecules CD11a/CD18 (integrin L/β2), CD11c/CD18 (integrin X/β2), CD31 (PECAM-1), CD48, and CD58 (LFA-3). Furthermore, B-CLL cells with 11q deletion expressed less the cell signaling receptors CD45 (leukocyte common antigen [LCA]), CD6, CD35 (complement receptor 1), and CD39. Reduced CD45 levels and low-level expression of CD49d correlated with decreased overall survival. B-CLL cells with or without 11q deletion did not differ in their growth fractions, expression levels of transcription factor NF-κB, or their response to mitogenic stimuli. Decreased levels of functionally relevant adhesion molecules and of cell signaling receptors may contribute to the pathogenesis of the subgroup of B-CLL characterized by 11q22-q23 deletion.

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