Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2748-2755 ◽  
Author(s):  
Jan Dürig ◽  
Holger Nückel ◽  
Andreas Hüttmann ◽  
Elisabeth Kruse ◽  
Tanja Hölter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Cell Clone ◽  
Expression Profiles ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Disease Stage ◽  
Unsupervised Hierarchical Cluster

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course. Recent studies have shown that CD38 surface expression on the malignant cell clone may serve as a prognostic marker in that CD38+ patients with B-CLL are characterized by advanced disease stage, lesser responsiveness to chemotherapy, and shorter survival than CD38− patients. To further investigate the molecular phenotype of these 2 clinical subgroups, we compared the gene expression profiles of CD38+ (n = 25) with CD38− (n = 45) B-CLL patients using oligonucleotide-based DNA chip microarrays representative of approximately 5600 genes. The results showed that B-CLLs display a common gene expression profile that is largely independent of CD38 expression. Nonetheless, the expression of 14 genes differed significantly between the 2 groups, including genes that are involved in the regulation of cell survival. Furthermore, unsupervised hierarchical cluster analysis of 76 B-CLL samples led to the separation of 2 major subgroups, comprising 20 and 56 patients. Clustering to the smaller group was due in part to the coordinate high expression of a large number of ribosomal and other translation-associated genes, including elongation factors. Importantly, we found that patients with high expression of translation factors were characterized by a more favorable clinical course with significantly longer progression-free survival and reduced chemotherapy requirements than the remaining patients (P < .05). Our data show that gene expression profiling can help identify B-CLL subtypes with different clinical characteristics. Furthermore, our results suggest a role of translation-associated genes in the pathogenesis of B-CLL.

scholarly journals Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2755-2763 ◽  
Author(s):  
Wee J. Chng ◽  
Roelandt F. Schop ◽  
Tammy Price-Troska ◽  
Irene Ghobrial ◽  
Neil Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Clone ◽  
Expression Profiles ◽  
Mapk Signaling ◽  
Lymphocytic Leukemia

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by the ability of the B-cell clone to differentiate into plasma cells. Although the clinical syndrome and the pathologic characteristics are well defined, little is known about its biology and controversy still exists regarding its cell of origin. In this gene-expression study, we compared the transcription profiles of WM with those of other malignant B cells including (chronic lymphocytic leukemia [CLL] and multiple myeloma [MM]) as well as normal cells (peripheral-blood B cells and bone marrow plasma cells). We found that WM has a homogenous gene expression regardless of 6q deletion status and clusters with CLL and normal B cells on unsupervised clustering with very similar expression profiles. Only a small gene set has expression profiles unique to WM compared to CLL and MM. The most significantly up-regulated gene is IL6 and the most significantly associated pathway for this set of genes is MAPK signaling. Thus, IL6 and its downstream signaling may be of biologic importance in WM. Further elucidation of the role of IL-6 in WM is warranted as this may offer a potential therapeutic avenue.

Functional Somatic and Germline Variants in the NF-κB Pathway in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 560-560 ◽  
Author(s):  
Ma. Reina Improgo ◽  
Adam Kiezun ◽  
Yaoyu Wang ◽  
Lillian Werner ◽  
Petar Stojanov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Transcriptional Activity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Lymphocytic Leukemia ◽  
Wild Type ◽  
Rt Pcr ◽  
Germline Variants

Abstract Abstract 560 Nuclear factor kappa B (NF-κB) encompasses a family of transcription factors involved in oncogenic processes including cellular proliferation and apoptotic inhibition. Constitutive activation of NF-κB has been observed in hematologic malignancies and is thought to confer resistance to chemotherapeutic agents. Here, we examine the role of the NF-κB pathway in chronic lymphocytic leukemia (CLL). Whole-exome sequencing was performed using tumor and matched germline DNA from 167 CLL patients. We identified 51 patients (30%) carrying 53 non-silent somatic variants in genes of the canonical NF-κB pathway, which consists of 272 genes as defined by the Ingenuity Pathway Analysis tool. Of the 99 patients whose germline sequences have been analyzed to date, 27 patients (27%) carry 34 non-silent germline variants in NF-κB pathway genes. A total of 67 patients (40%) have at least one non-silent somatic or germline variant. Variants in the NFKB1 gene, itself, were also observed: a somatic variant, H66R, found in two patients, and two germline variants, Y89F and R849W, each found in one patient. To evaluate the functional consequences of the NFKB1 variants, we performed site-directed mutagenesis to generate full-length NFKB1 cDNAs encoding these variants. We subsequently measured transcriptional activity of wild-type and mutant NFKB1 via luciferase assays in HEK293T cells using reporter cassettes containing the NFKB1 response element. Transcriptional activity of the three NFKB1 variants was found to be at least 2-fold higher than that of wild-type NFKB1 (p<0.0001). We further hypothesized that this increased transcriptional activity would lead to increased expression of NFKB1 downstream target genes. Analysis of gene expression profiles from Affymetrix HG-U133 Plus 2.0 Arrays of 65 CLL patient samples showed that the NFKB1 downstream targets CCL3, CCL4, and CD69 are upregulated in NFKB1 variants. To validate these results, we performed quantitative RT-PCR in patients with (n=3) or without (n=9) NFKB1 variants and confirmed upregulation of CCL3 (p=0.0286), CCL4 (p=0.0384), and CD69 (p=0.0263). Direct transfection of HEK293T cells with NFKB1 variants also resulted in a 3.3-fold upregulation of CCL3 (p=0.05). To test the hypothesis that deregulation of the NF-κB pathway is a key mechanism in CLL, we compared gene expression profiles of NF-κB pathway genes between CLL patient samples (n=146) and normal B cells (n=16) and found overall upregulation of the NF-κB pathway in CLL (Kolmogorov-Smirnov test, p=2.2e-16). K-means clustering and principal component analysis (PCA) further revealed that CLL patients can be divided into two subgroups exhibiting differential magnitude of NF-κB pathway upregulation. Studies in progress aim to identify the clinical significance of these subgroups. Finally, we assessed the effect of inhibiting the NF-κB pathway using the cell permeant NF-κB inhibitor, SN50. We performed Annexin V/PI staining 24 hours post-treatment in CLL cells with (n=9) or without (n=3) NF-κB pathway variants. SN50 increased cell death 1.8-fold in all cells tested (p<0.0001). Quantitative RT-PCR also showed a 59% decrease in expression of CCL3 one hour post-treatment, confirming inhibition of the NF-κB pathway. In conclusion, our findings demonstrate that a high proportion of CLL patients harbor somatic and germline variants in NF-κB pathway genes, some of which appear to be functional. Furthermore, the NF-κB pathway is upregulated in CLL and pharmacological inhibition of the pathway leads to increased cancer cell death. Functional characterization of NF-κB pathway variants offers mechanistic insight into the disease, providing novel targets for therapy. Disclosures: No relevant conflicts of interest to declare.

Stereotyped Subset #4 In Chronic Lymphocytic Leukemia Is Associated With Distinct Gene and Microrna Transcriptional Profile

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1616-1616
Author(s):  
Francesco Maura ◽  
Laura Mosca ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
Marta Lionetti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mirna Expression ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Distinct Gene ◽  
Mirna Expression Pattern

Abstract Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the monoclonal accumulation of B lymphocytes and a variable clinical course. Specific B-Cell Receptor (BCR) utilized by leukemic cells may influence disease progression and outcome. Highly homologous BCR, “stereotyped BCR”, are expressed in a recurrent fraction of patients with CLL and in some cases they were associated with distinct biological and clinical features. Stereotyped subset #4 have been reported to exhibit a favorable clinical course and to be the most frequent stereotyped BCR among the IGHV mutated (IGHV-M) cases. In this study we performed a comprehensive clinical, biological and molecular characterization of leukemic cells from 16 patients utilizing stereotyped subset #4 BCR (IGHV4-34) among a representative prospective cohort of 462 Binet stage A CLL patients enrolled in O-CLL1 protocol (clinicaltrial.gov identifier NCT00917540). In all cases, biological and molecular analyses were performed in peripheral CD19+ B-cells. All subset #4 patients were characterized by lower CD38 expression, unique IGHV-M configuration and absence of NOTCH1 and SF3B1 mutations. None subset #4 patients showed unfavorable cytogenetic deletions (i.e del11q23 and del17p13). Gene expression profiling (GEP) analysis was performed on 217 patients, including 9 subset #4 cases for whom RNA material was available. Supervised analysis comparing subset #4 vs all other patients (208) revealed 14 differentially expressed genes. Furthermore subset #4 patients were characterized by a significant downregulation of WDFY4, MEF2A and upregulation of PDGFA, FGFR1 and TFEC genes when compared with the remaining IGHV-M patients. miRNA profiles were analyzed in 229 patients including 10 subset #4 patients for whom RNA material was available. A specific miRNA expression pattern involving the upregulation of miR-497 and miR-29c was found in subset# 4 cases. Furthermore, we demonstrated that transfection of the miR-497 mimic in primary leukemic CLL cells induces, after 48 and/or 72 h, a downregulation of BCL2, known to be a validated target in different solid cancers. Our data provide a contribution to the biological definition of CLL patients with specific stereotyped IGHV4-34 BCR and identify for the first time distinct gene and miRNA expression profiles associated with this subset, providing further evidence of the putative leading role of HCDR3 conformation in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2639-2649 ◽  
Author(s):  
Han-Yu Chuang ◽  
Laura Rassenti ◽  
Michelle Salcedo ◽  
Kate Licon ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Lymphocytic Leukemia ◽  
Cancer Evolution ◽  
Sample Collection ◽  
Over Time

Abstract The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on 2 other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points before therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL.

scholarly journals Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients

Haematologica ◽  
2021 ◽  
Author(s):  
Johannes Bloehdorn ◽  
Julia Krzykalla ◽  
Karlheinz Holzmann ◽  
Andreas Gerhardinger ◽  
Billy Michael Chelliah Jebaraj ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Expression Profiling ◽  
Heavy Chain ◽  
Expression Profiling ◽  
Progression Free Survival ◽  
Immunoglobulin Heavy Chain ◽  
Lymphocytic Leukemia ◽  
Prognostic Models ◽  
Variable Gene

Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab can induce longterm remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to fludarabine, cyclophosphamide and rituximab in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable gene. To identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab, we developed integrative models including established prognostic parameters and gene expression profiling. Gene expression profiling was conducted on n=337 CLL8 trial samples, “core” probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and immunoglobulin heavy chain variable gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and gene expression profiling variables performed equal to models including only established non-gene expression profiling variables. Gene expression profiling variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the immunoglobulin heavy chain variable gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. Gene expression profiling based prognostic models can help to identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab treatment. The CLL8 trial is registered under EUDRACT- 2004-004938-14 and ClinicalTrials.gov Identifier NCT00281918.

scholarly journals Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia

2014 ◽  
Author(s):  
Simone Ecker ◽  
Vera Pancaldi ◽  
Daniel Rico ◽  
Alfonso Valencia
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cellular Communication ◽  
Lymphocytic Leukemia ◽  
Resistance To Therapy ◽  
Expression Variability ◽  
Disease Subtype ◽  
Aggressive Subtype

Background: Chronic Lymphocytic Leukemia (CLL) presents two subtypes which have drastically different clinical outcomes. So far, these two subtypes are not associated to clear differences in gene expression profiles. Interestingly, recent results have highlighted important roles for heterogeneity, both at the genetic and at the epigenetic level in CLL progression. Results: We propose to use gene expression variability across patients to investigate differences between the two CLL subtypes. We find that the most aggressive type of this disease shows higher variability of gene expression across patients and we elaborate on this observation to produce a method that classifies patients into clinical subtypes. Finally, we find that, overall, genes that show higher variability in the aggressive subtype are related to cell cycle, development and inter-cellular communication, probably related to faster progression of this disease subtype. Conclusions: There are strong relations between disease subtype and gene expression variability linking significantly increased expression variability to phenotypes such as aggressiveness and resistance to therapy in CLL.

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